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Inflammation of the Skin and Its Therapeutic Targets

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Abstract

The skin is a formidable physical barrier that protects the body from infection and other foreign irritants. Immune cells in the skin play a critical role in host defense, and include a number of specialized cell types such as keratinocytes, Langerhans cells, dendritic cells, and various subsets of T cells, which aid the body in fighting pathogens. However, when immune function in the skin is compromised, either due to a hereditary defect in skin barrier function, or as a result of unwarranted immune sensitization, these same cells can drive the development of skin disease and induce chronic cutaneous inflammation. In this chapter, we will review the immunological functions of the skin and discuss the roles of various immune cells and cellular mediators in host defense. Next, we will examine in detail the immunological basis and pathophysiology of two widely prevalent skin diseases mediated by immune cells, namely atopic dermatitis and psoriasis. The immunopathogenesis of these diseases will be discussed in light of current evidence from the literature and the roles of various subsets of helper T cells, including TH2, TH17, and TH22 cells will be highlighted. Lastly, we will examine the pharmacology of various immunotherapeutic drugs used in the treatment of these diseases. These include glucocorticoids, anti-proliferative agents, phosphodiesterase inhibitors, and various biologics such as inhibitors of IL-4, IL-13, IL-17, and IL-12 and IL-23. In the From Bench to Bedside section, we will review the discovery and development of Dupilumab for the treatment of atopic dermatitis.

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Suggested Reading

  • AbuHilal M, Walsh S, Shear N. The role of IL-17 in the pathogenesis of psoriasis and update on IL-17 inhibitors for the treatment of plaque psoriasis. J Cutan Med Surg. 2016;20:509–16.

    Article  CAS  PubMed  Google Scholar 

  • Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol. 2007;8:942–9.

    Article  CAS  PubMed  Google Scholar 

  • Akdis CA, Akdis M. Immunological differences between intrinsic and extrinsic types of atopic dermatitis. Clin Exp Allergy. 2003;33:1618–21.

    Article  CAS  PubMed  Google Scholar 

  • Akdis CA, et al. Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL consensus report. Allergy. 2006;61:969–87.

    Article  CAS  PubMed  Google Scholar 

  • Amano W, et al. The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling. J Allergy Clin Immunol. 2015;136:667–77.e667.

    Article  CAS  PubMed  Google Scholar 

  • Armstrong AW, et al. Effect of ixekizumab treatment on work productivity for patients with moderate-to-severe plaque psoriasis: analysis of results from 3 randomized phase 3 clinical trials. JAMA Dermatol. 2016;152:661–9.

    Article  PubMed  Google Scholar 

  • Bao L, Zhang H, Chan LS. The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis. JAKSTAT. 2013;2:e24137.

    PubMed  PubMed Central  Google Scholar 

  • Beck LA, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014;371:130–9.

    Article  PubMed  CAS  Google Scholar 

  • Bissonnette R, et al. Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial. Br J Dermatol. 2016;175:902–11.

    Article  CAS  PubMed  Google Scholar 

  • Blauvelt A, Chiricozzi A. The immunologic role of IL-17 in psoriasis and psoriatic arthritis pathogenesis. Clin Rev Allergy Immunol. 2018;55:379–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blauvelt A, et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate-to-severe plaque psoriasis up to 1 year: results from the CLEAR study. J Am Acad Dermatol. 2017;76:60–9.e69.

    Article  CAS  PubMed  Google Scholar 

  • Bonefeld CM, Geisler C. The role of innate lymphoid cells in healthy and inflamed skin. Immunol Lett. 2016;179:25–8.

    Article  CAS  PubMed  Google Scholar 

  • Bruggen MC, et al. In situ mapping of innate lymphoid cells in human skin: evidence for remarkable differences between Normal and inflamed skin. J Invest Dermatol. 2016;136:2396–405.

    Article  PubMed  CAS  Google Scholar 

  • Brunner PM, et al. A mild topical steroid leads to progressive anti-inflammatory effects in the skin of patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol. 2016;138:169–78.

    Article  CAS  PubMed  Google Scholar 

  • Brunner PM, Guttman-Yassky E, Leung DY. The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies. J Allergy Clin Immunol. 2017a;139:S65–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brunner PM, et al. Increasing comorbidities suggest that atopic dermatitis is a systemic disorder. J Invest Dermatol. 2017b;137:18–25.

    Article  CAS  PubMed  Google Scholar 

  • Brunner PM, et al. Early-onset pediatric atopic dermatitis is characterized by TH2/TH17/TH22-centered inflammation and lipid alterations. J Allergy Clin Immunol. 2018;141:2094–106.

    Article  CAS  PubMed  Google Scholar 

  • Castro M, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018;378:2486–96.

    Article  CAS  PubMed  Google Scholar 

  • Chalmers JR, et al. Report from the fifth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative). Br J Dermatol. 2018;178:e332–41.

    Article  CAS  PubMed  Google Scholar 

  • Cherwinski HM, Schumacher JH, Brown KD, Mosmann TR. Two types of mouse helper T cell clone. III. Further differences in lymphokine synthesis between Th1 and Th2 clones revealed by RNA hybridization, functionally monospecific bioassays, and monoclonal antibodies. J Exp Med. 1987;166:1229–44.

    Article  CAS  PubMed  Google Scholar 

  • Coffman RL. Converging discoveries: the first reports of IL-4. J Immunol. 2013;190:847–8.

    Article  CAS  PubMed  Google Scholar 

  • Cole C, et al. Filaggrin-stratified transcriptomic analysis of pediatric skin identifies mechanistic pathways in patients with atopic dermatitis. J Allergy Clin Immunol. 2014;134:82–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Czarnowicki T, Krueger JG, Guttman-Yassky E. Skin barrier and immune dysregulation in atopic dermatitis: an evolving story with important clinical implications. J Allergy Clin Immunol Pract. 2014;2:371–9;. quiz 380-371.

    Article  PubMed  Google Scholar 

  • Czarnowicki T, Krueger JG, Guttman-Yassky E. Novel concepts of prevention and treatment of atopic dermatitis through barrier and immune manipulations with implications for the atopic march. J Allergy Clin Immunol. 2017;139:1723–34.

    Article  CAS  PubMed  Google Scholar 

  • Davis DM, Borok J, Udkoff J, Lio P, Spergel J. Atopic dermatitis: phototherapy and systemic therapy. Semin Cutan Med Surg. 2017;36:118–23.

    Article  PubMed  Google Scholar 

  • Dong J, Goldenberg G. New biologics in psoriasis: an update on IL-23 and IL-17 inhibitors. Cutis. 2017;99:123–7.

    PubMed  Google Scholar 

  • Duhen T, Geiger R, Jarrossay D, Lanzavecchia A, Sallusto F. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol. 2009;10:857–63.

    Article  CAS  PubMed  Google Scholar 

  • Egawa G, Kabashima K. Multifactorial skin barrier deficiency and atopic dermatitis: essential topics to prevent the atopic march. J Allergy Clin Immunol. 2016;138:350–8.e351.

    Article  PubMed  Google Scholar 

  • Egeberg A. Phase 3 trials of Ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016;375:2101–2.

    Article  PubMed  Google Scholar 

  • Eichenfield LF, Stein Gold LF. Systemic therapy of atopic dermatitis: welcome to the revolution. Semin Cutan Med Surg. 2017;36:S103–5.

    PubMed  Google Scholar 

  • Eichenfield LF, et al. Long-term safety of crisaborole ointment 2% in children and adults with mild to moderate atopic dermatitis. J Am Acad Dermatol. 2017;77:641–9.e645.

    Article  CAS  PubMed  Google Scholar 

  • Esaki H, et al. Early-onset pediatric atopic dermatitis is TH2 but also TH17 polarized in skin. J Allergy Clin Immunol. 2016;138:1639–51.

    Article  CAS  PubMed  Google Scholar 

  • Eyerich K, et al. IL-17 in atopic eczema: linking allergen-specific adaptive and microbial-triggered innate immune response. J Allergy Clin Immunol. 2009a;123:59–66.e54.

    Article  CAS  PubMed  Google Scholar 

  • Eyerich S, et al. Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J Clin Invest. 2009b;119:3573–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Eyerich S, et al. Mutual antagonism of T cells causing psoriasis and atopic eczema. N Engl J Med. 2011;365:231–8.

    Article  CAS  PubMed  Google Scholar 

  • Eyerich K, Dimartino V, Cavani A. IL-17 and IL-22 in immunity: driving protection and pathology. Eur J Immunol. 2017;47:607–14.

    Article  CAS  PubMed  Google Scholar 

  • Furue M, Kadono T. “Inflammatory skin march” in atopic dermatitis and psoriasis. Inflamm Res. 2017;66:833–42.

    Article  CAS  PubMed  Google Scholar 

  • Ganguly D, et al. Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. J Exp Med. 2009;206:1983–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gisondi P, Girolomoni G. Apremilast in the therapy of moderate-to-severe chronic plaque psoriasis. Drug Des Devel Ther. 2016;10:1763–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gittler JK, et al. Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin Immunol. 2012;130:1344–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Glatzer F, et al. Histamine induces proliferation in keratinocytes from patients with atopic dermatitis through the histamine 4 receptor. J Allergy Clin Immunol. 2013;132:1358–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gordon KB, Colombel JF, Hardin DS. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016a;375:2102.

    Article  PubMed  Google Scholar 

  • Gordon KB, et al. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016b;375:345–56.

    Article  CAS  PubMed  Google Scholar 

  • Gottlieb AB, et al. Efficacy, tolerability, and pharmacodynamics of apremilast in recalcitrant plaque psoriasis: a phase II open-label study. J Drugs Dermatol. 2013;12:888–97.

    CAS  PubMed  Google Scholar 

  • Griffin GK, et al. IL-17 and TNF-alpha sustain neutrophil recruitment during inflammation through synergistic effects on endothelial activation. J Immunol. 2012;188:6287–99.

    Article  CAS  PubMed  Google Scholar 

  • Grunig G, et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science. 1998;282:2261–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gutowska-Owsiak D, et al. IL-17 downregulates filaggrin and affects keratinocyte expression of genes associated with cellular adhesion. Exp Dermatol. 2012;21:104–10.

    Article  CAS  PubMed  Google Scholar 

  • Guttman-Yassky E, Krueger JG, Lebwohl MG. Systemic immune mechanisms in atopic dermatitis and psoriasis with implications for treatment. Exp Dermatol. 2018;27:409–17.

    Article  PubMed  Google Scholar 

  • Halim TY, et al. Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation. Immunity. 2014;40:425–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hamid Q, Boguniewicz M, Leung DY. Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis. J Clin Invest. 1994;94:870–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hamilton JD, et al. Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol. 2014;134:1293–300.

    Article  CAS  PubMed  Google Scholar 

  • Hanifin JM, Reed ML, Eczema P, Impact Working G. A population-based survey of eczema prevalence in the United States. Dermatitis. 2007;18:82–91.

    Article  PubMed  Google Scholar 

  • He JQ, et al. Genetic variants of the IL13 and IL4 genes and atopic diseases in at-risk children. Genes Immun. 2003;4:385–9.

    Article  CAS  PubMed  Google Scholar 

  • Hijnen DJ, ten Berge O, Timmer-de Mik L, Bruijnzeel-Koomen CA, de Bruin-Weller MS. Efficacy and safety of long-term treatment with cyclosporin A for atopic dermatitis. J Eur Acad Dermatol Venereol. 2007;21:85–9.

    Article  CAS  PubMed  Google Scholar 

  • Howard M, et al. Identification of a T cell-derived b cell growth factor distinct from interleukin 2. J Exp Med. 1982;155:914–23.

    Article  CAS  PubMed  Google Scholar 

  • Howell MD, et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol. 2009;124:R7–R12.

    Article  CAS  PubMed  Google Scholar 

  • Howell MD, Parker ML, Mustelin T, Ranade K. Past, present, and future for biologic intervention in atopic dermatitis. Allergy. 2015;70:887–96.

    Article  CAS  PubMed  Google Scholar 

  • Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med. 2011;365:1315–27.

    Article  CAS  PubMed  Google Scholar 

  • Isakson PC, Pure E, Vitetta ES, Krammer PH. T cell-derived B cell differentiation factor(s). Effect on the isotype switch of murine B cells. J Exp Med. 1982;155:734–48.

    Article  CAS  PubMed  Google Scholar 

  • Iwakura Y, Ishigame H, Saijo S, Nakae S. Functional specialization of interleukin-17 family members. Immunity. 2011;34:149–62.

    Article  CAS  PubMed  Google Scholar 

  • Iwasaki M, et al. Association of a new-type prostaglandin D2 receptor CRTH2 with circulating T helper 2 cells in patients with atopic dermatitis. J Invest Dermatol. 2002;119:609–16.

    Article  CAS  PubMed  Google Scholar 

  • Jones PT, Dear PH, Foote J, Neuberger MS, Winter G. Replacing the complementarity-determining regions in a human antibody with those from a mouse. Nature. 1986;321:522–5.

    Article  CAS  PubMed  Google Scholar 

  • Kagami S, Rizzo HL, Lee JJ, Koguchi Y, Blauvelt A. Circulating Th17, Th22, and Th1 cells are increased in psoriasis. J Invest Dermatol. 2010;130:1373–83.

    Article  CAS  PubMed  Google Scholar 

  • Khattri S, et al. Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology. J Allergy Clin Immunol. 2014;133:1626–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khattri S, et al. Efficacy and safety of ustekinumab treatment in adults with moderate-to-severe atopic dermatitis. Exp Dermatol. 2017;26:28–35.

    Article  CAS  PubMed  Google Scholar 

  • Kim BS, et al. TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. Sci Transl Med. 2013;5:170ra116.

    Article  CAS  Google Scholar 

  • Kim J, et al. Epidermal thymic stromal lymphopoietin predicts the development of atopic dermatitis during infancy. J Allergy Clin Immunol. 2016;137:1282–5.e1284.

    Article  CAS  PubMed  Google Scholar 

  • Kopp T, et al. Clinical improvement in psoriasis with specific targeting of interleukin-23. Nature. 2015;521:222–6.

    Article  CAS  PubMed  Google Scholar 

  • Kupetsky EA, Mathers AR, Ferris LK. Anti-cytokine therapy in the treatment of psoriasis. Cytokine. 2013;61:704–12.

    Article  CAS  PubMed  Google Scholar 

  • Lande R, et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 2007;449:564–9.

    Article  CAS  PubMed  Google Scholar 

  • Lande R, et al. The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis. Nat Commun. 2014;5:5621.

    Article  CAS  PubMed  Google Scholar 

  • Langley RG, et al. Secukinumab in plaque psoriasis—results of two phase 3 trials. N Engl J Med. 2014;371:326–38.

    Article  CAS  PubMed  Google Scholar 

  • Lebwohl M, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med. 2015;373:1318–28.

    Article  CAS  PubMed  Google Scholar 

  • Lee F, et al. Isolation and characterization of a mouse interleukin cDNA clone that expresses B-cell stimulatory factor 1 activities and T-cell- and mast-cell-stimulating activities. Proc Natl Acad Sci U S A. 1986;83:2061–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leung DY, Guttman-Yassky E. Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches. J Allergy Clin Immunol. 2014;134:769–79.

    Article  PubMed  PubMed Central  Google Scholar 

  • Levy LL, Urban J, King BA. Treatment of recalcitrant atopic dermatitis with the oral Janus kinase inhibitor tofacitinib citrate. J Am Acad Dermatol. 2015;73:395–9.

    Article  CAS  PubMed  Google Scholar 

  • Lopez-Ferrer A, Vilarrasa E, Gich IJ, Puig L. Adalimumab for the treatment of psoriasis in real life: a retrospective cohort of 119 patients at a single Spanish centre. Br J Dermatol. 2013;169:1141–7.

    Article  CAS  PubMed  Google Scholar 

  • Lopez-Ferrer A, Vilarrasa E, Puig L. Secukinumab (AIN457) for the treatment of psoriasis. Expert Rev Clin Immunol. 2015;11:1177–88.

    Article  CAS  PubMed  Google Scholar 

  • Margolis DJ, et al. The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort. J Allergy Clin Immunol. 2012;130:912–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McAleer MA, Irvine AD. The multifunctional role of filaggrin in allergic skin disease. J Allergy Clin Immunol. 2013;131:280–91.

    Article  CAS  PubMed  Google Scholar 

  • McKenzie AN, et al. Interleukin 13, a T-cell-derived cytokine that regulates human monocyte and B-cell function. Proc Natl Acad Sci U S A. 1993;90:3735–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mease PJ, et al. Secukinumab inhibition of interleukin-17A in patients with psoriatic arthritis. N Engl J Med. 2015;373:1329–39.

    Article  CAS  PubMed  Google Scholar 

  • Mease PJ, et al. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann Rheum Dis. 2017;76:79–87.

    Article  CAS  PubMed  Google Scholar 

  • Mennini M, Dahdah L, Fiocchi A. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2017;376:1090.

    Article  PubMed  Google Scholar 

  • Menter A, et al. Efficacy of ixekizumab compared to etanercept and placebo in patients with moderate-to-severe plaque psoriasis and non-pustular palmoplantar involvement: results from three phase 3 trials (UNCOVER-1, UNCOVER-2 and UNCOVER-3). J Eur Acad Dermatol Venereol. 2017;31:1686–92.

    Article  CAS  PubMed  Google Scholar 

  • Minty A, et al. Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses. Nature. 1993;362:248–50.

    Article  CAS  PubMed  Google Scholar 

  • Montaldo E, Juelke K, Romagnani C. Group 3 innate lymphoid cells (ILC3s): origin, differentiation, and plasticity in humans and mice. Eur J Immunol. 2015;45:2171–82.

    Article  CAS  PubMed  Google Scholar 

  • Moreno AS, McPhee R, Arruda LK, Howell MD. Targeting the T helper 2 inflammatory axis in atopic dermatitis. Int Arch Allergy Immunol. 2016;171:71–80.

    Article  CAS  PubMed  Google Scholar 

  • Morgan JG, Dolganov GM, Robbins SE, Hinton LM, Lovett M. The selective isolation of novel cDNAs encoded by the regions surrounding the human interleukin 4 and 5 genes. Nucleic Acids Res. 1992;20:5173–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morrison SL, Johnson MJ, Herzenberg LA, Oi VT. Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. Proc Natl Acad Sci U S A. 1984;81:6851–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986;136:2348–57.

    CAS  PubMed  Google Scholar 

  • Nakajima S, et al. Langerhans cells are critical in epicutaneous sensitization with protein antigen via thymic stromal lymphopoietin receptor signaling. J Allergy Clin Immunol. 2012;129:1048–1055 e1046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nast A, Jacobs A, Rosumeck S, Werner RN. Efficacy and safety of systemic long-term treatments for moderate-to-severe psoriasis: a systematic review and meta-analysis. J Invest Dermatol. 2015;135:2641–8.

    Article  CAS  PubMed  Google Scholar 

  • Nemoto O, et al. The first trial of CIM331, a humanized antihuman interleukin-31 receptor A antibody, in healthy volunteers and patients with atopic dermatitis to evaluate safety, tolerability and pharmacokinetics of a single dose in a randomized, double-blind, placebo-controlled study. Br J Dermatol. 2016;174:296–304.

    Article  CAS  PubMed  Google Scholar 

  • Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009;361:496–509.

    Article  CAS  PubMed  Google Scholar 

  • Niebuhr M, Scharonow H, Gathmann M, Mamerow D, Werfel T. Staphylococcal exotoxins are strong inducers of IL-22: a potential role in atopic dermatitis. J Allergy Clin Immunol. 2010;126:1176–83.e1174.

    Article  CAS  PubMed  Google Scholar 

  • Noda S, Krueger JG, Guttman-Yassky E. The translational revolution and use of biologics in patients with inflammatory skin diseases. J Allergy Clin Immunol. 2015a;135:324–36.

    Article  CAS  PubMed  Google Scholar 

  • Noda S, et al. The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization. J Allergy Clin Immunol. 2015b;136:1254–64.

    Article  CAS  PubMed  Google Scholar 

  • Nograles KE, et al. Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. Br J Dermatol. 2008;159:1092–102.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nograles KE, et al. IL-22-producing “T22” T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells. J Allergy Clin Immunol. 2009;123:1244–52.e1242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Noma Y, et al. Cloning of cDNA encoding the murine IgG1 induction factor by a novel strategy using SP6 promoter. Nature. 1986;319:640–6.

    Article  CAS  PubMed  Google Scholar 

  • Nomura I, et al. Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J Immunol. 2003;171:3262–9.

    Article  CAS  PubMed  Google Scholar 

  • Oldhoff JM, et al. Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis. Allergy. 2005;60:693–6.

    Article  CAS  PubMed  Google Scholar 

  • Oliva M, Renert-Yuval Y, Guttman-Yassky E. The ‘omics’ revolution: redefining the understanding and treatment of allergic skin diseases. Curr Opin Allergy Clin Immunol. 2016;16:469–76.

    Article  CAS  PubMed  Google Scholar 

  • Ong PY, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med. 2002;347:1151–60.

    Article  CAS  PubMed  Google Scholar 

  • Oppmann B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000;13:715–25.

    Article  CAS  PubMed  Google Scholar 

  • Paller AS, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016;75:494–503.e496.

    Article  CAS  PubMed  Google Scholar 

  • Papp KA, et al. A prospective phase III, randomized, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis. Br J Dermatol. 2016;175:273–86.

    Article  CAS  PubMed  Google Scholar 

  • Parham C, et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol. 2002;168:5699–708.

    Article  CAS  PubMed  Google Scholar 

  • Perez-Aso M, et al. Apremilast, a novel phosphodiesterase 4 (PDE4) inhibitor, regulates inflammation through multiple cAMP downstream effectors. Arthritis Res Ther. 2015;17:249.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pincelli C, Schafer PH, French LE, Augustin M, Krueger JG. Mechanisms underlying the clinical effects of apremilast for psoriasis. J Drugs Dermatol. 2018;17:835–40.

    CAS  PubMed  Google Scholar 

  • Puig L, Lopez A, Vilarrasa E, Garcia I. Efficacy of biologics in the treatment of moderate-to-severe plaque psoriasis: a systematic review and meta-analysis of randomized controlled trials with different time points. J Eur Acad Dermatol Venereol. 2014;28:1633–53.

    Article  CAS  PubMed  Google Scholar 

  • Rabenhorst A, Hartmann K. Interleukin-31: a novel diagnostic marker of allergic diseases. Curr Allergy Asthma Rep. 2014;14:423.

    Article  PubMed  CAS  Google Scholar 

  • Robinson DS, et al. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med. 1992;326:298–304.

    Article  CAS  PubMed  Google Scholar 

  • Samrao A, Berry TM, Goreshi R, Simpson EL. A pilot study of an oral phosphodiesterase inhibitor (apremilast) for atopic dermatitis in adults. Arch Dermatol. 2012;148:890–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schafer P. Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. Biochem Pharmacol. 2012;83:1583–90.

    Article  CAS  PubMed  Google Scholar 

  • Schafer PH, et al. Apremilast is a selective PDE4 inhibitor with regulatory effects on innate immunity. Cell Signal. 2014;26:2016–29.

    Article  CAS  PubMed  Google Scholar 

  • Schafer PH, Chen P, Fang L, Wang A, Chopra R. The pharmacodynamic impact of apremilast, an oral phosphodiesterase 4 inhibitor, on circulating levels of inflammatory biomarkers in patients with psoriatic arthritis: substudy results from a phase III, randomized, placebo-controlled trial (PALACE 1). J Immunol Res. 2015;2015:906349.

    Article  PubMed  PubMed Central  Google Scholar 

  • Schafer PH, et al. Phosphodiesterase 4 in inflammatory diseases: effects of apremilast in psoriatic blood and in dermal myofibroblasts through the PDE4/CD271 complex. Cell Signal. 2016;28:753–63.

    Article  CAS  PubMed  Google Scholar 

  • Schurich A, Raine C, Morris V, Ciurtin C. The role of IL-12/23 in T cell-related chronic inflammation: implications of immunodeficiency and therapeutic blockade. Rheumatology (Oxford). 2018;57:246–54.

    Article  CAS  Google Scholar 

  • Sehra S, et al. IL-4 regulates skin homeostasis and the predisposition toward allergic skin inflammation. J Immunol. 2010;184:3186–90.

    Article  CAS  PubMed  Google Scholar 

  • Silverberg JI. Persistence of childhood eczema into adulthood. JAMA Dermatol. 2014;150:591–2.

    Article  PubMed  Google Scholar 

  • Silverberg JI. Association between adult atopic dermatitis, cardiovascular disease, and increased heart attacks in three population-based studies. Allergy. 2015;70:1300–8.

    Article  CAS  PubMed  Google Scholar 

  • Silverberg JI, Simpson EL. Associations of childhood eczema severity: a US population-based study. Dermatitis. 2014;25:107–14.

    Article  PubMed  PubMed Central  Google Scholar 

  • Simon D. Systemic therapy of atopic dermatitis in children and adults. Curr Probl Dermatol. 2011;41:156–64.

    Article  CAS  PubMed  Google Scholar 

  • Simon D, Bieber T. Systemic therapy for atopic dermatitis. Allergy. 2014;69:46–55.

    Article  CAS  PubMed  Google Scholar 

  • Simpson EL, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375:2335–48.

    Article  CAS  PubMed  Google Scholar 

  • Simpson EL, Akinlade B, Ardeleanu M. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2017a;376:1090–1.

    Article  PubMed  Google Scholar 

  • Simpson EL, et al. When does atopic dermatitis warrant systemic therapy? Recommendations from an expert panel of the International Eczema Council. J Am Acad Dermatol. 2017b;77:623–33.

    Article  PubMed  Google Scholar 

  • Slater NA, Morrell DS. Systemic therapy of childhood atopic dermatitis. Clin Dermatol. 2015;33:289–99.

    Article  PubMed  Google Scholar 

  • Sofen H, et al. Guselkumab (an IL-23-specific mAb) demonstrates clinical and molecular response in patients with moderate-to-severe psoriasis. J Allergy Clin Immunol. 2014;133:1032–40.

    Article  CAS  PubMed  Google Scholar 

  • Sonnenberg GF, Fouser LA, Artis D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat Immunol. 2011;12:383–90.

    Article  CAS  PubMed  Google Scholar 

  • Spertino J, Lopez-Ferrer A, Vilarrasa E, Puig L. Long-term study of infliximab for psoriasis in daily practice: drug survival depends on combined treatment, obesity and infusion reactions. J Eur Acad Dermatol Venereol. 2014;28:1514–21.

    Article  CAS  PubMed  Google Scholar 

  • Suarez-Farinas M, et al. Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis. J Allergy Clin Immunol. 2013;132:361–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thaci D, et al. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial. Lancet. 2016;387:40–52.

    Article  CAS  PubMed  Google Scholar 

  • Torres T, Romanelli M, Chiricozzi A. A revolutionary therapeutic approach for psoriasis: bispecific biological agents. Expert Opin Investig Drugs. 2016;25:751–4.

    Article  CAS  PubMed  Google Scholar 

  • Ulven T, Kostenis E. Novel CRTH2 antagonists: a review of patents from 2006 to 2009. Expert Opin Ther Pat. 2010;20:1505–30.

    Article  CAS  PubMed  Google Scholar 

  • van de Kerkhof PC, et al. Secukinumab long-term safety experience: a pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis. J Am Acad Dermatol. 2016;75:83–98.e84.

    Article  PubMed  CAS  Google Scholar 

  • Veilleux MS, Shear NH. Biologics in patients with skin diseases. J Allergy Clin Immunol. 2017;139:1423–30.

    Article  PubMed  Google Scholar 

  • Vena GA, Vestita M, Cassano N. Psoriasis and cardiovascular disease. Dermatol Ther. 2010;23:144–51.

    Article  PubMed  Google Scholar 

  • Vilarrasa E, et al. ORBIT (outcome and retention rate of biologic treatments for psoriasis): a retrospective observational study on biologic drug survival in daily practice. J Am Acad Dermatol. 2016;74:1066–72.

    Article  PubMed  Google Scholar 

  • Volf EM, Au SC, Dumont N, Scheinman P, Gottlieb AB. A phase 2, open-label, investigator-initiated study to evaluate the safety and efficacy of apremilast in subjects with recalcitrant allergic contact or atopic dermatitis. J Drugs Dermatol. 2012;11:341–6.

    CAS  PubMed  Google Scholar 

  • Walker C, et al. Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage. Am Rev Respir Dis. 1992;146:109–15.

    Article  CAS  PubMed  Google Scholar 

  • Wang YH, Liu YJ. Thymic stromal lymphopoietin, OX40-ligand, and interleukin-25 in allergic responses. Clin Exp Allergy. 2009;39:798–806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Welsch K, Holstein J, Laurence A, Ghoreschi K. Targeting JAK/STAT signalling in inflammatory skin diseases with small molecule inhibitors. Eur J Immunol. 2017;47:1096–107.

    Article  CAS  PubMed  Google Scholar 

  • Werfel T, Biedermann T. Current novel approaches in systemic therapy of atopic dermatitis: specific inhibition of cutaneous Th2 polarized inflammation and itch. Curr Opin Allergy Clin Immunol. 2015;15:446–52.

    Article  CAS  PubMed  Google Scholar 

  • Werfel T, et al. Cellular and molecular immunologic mechanisms in patients with atopic dermatitis. J Allergy Clin Immunol. 2016;138:336–49.

    Article  CAS  PubMed  Google Scholar 

  • Wills-Karp M, et al. Interleukin-13: central mediator of allergic asthma. Science. 1998;282:2258–61.

    Article  CAS  PubMed  Google Scholar 

  • Wolk K, et al. IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. Eur J Immunol. 2006;36:1309–23.

    Article  CAS  PubMed  Google Scholar 

  • Wollenberg A, et al. Treatment of atopic dermatitis with tralokinumab, an anti-IL-13 mAb. J Allergy Clin Immunol. 2019;143:135–41.

    Article  CAS  PubMed  Google Scholar 

  • Yiu ZZ, Warren RB. Novel Oral therapies for psoriasis and psoriatic arthritis. Am J Clin Dermatol. 2016;17:191–200.

    Article  PubMed  Google Scholar 

  • Zheng T, et al. Transgenic expression of interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling. J Invest Dermatol. 2009;129:742–51.

    Article  CAS  PubMed  Google Scholar 

  • Ziegler SF, Liu YJ. Thymic stromal lymphopoietin in normal and pathogenic T cell development and function. Nat Immunol. 2006;7:709–14.

    Article  CAS  PubMed  Google Scholar 

  • Zurawski SM, Vega F Jr, Huyghe B, Zurawski G. Receptors for interleukin-13 and interleukin-4 are complex and share a novel component that functions in signal transduction. EMBO J. 1993;12:2663–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Mathias, C.B. (2020). Inflammation of the Skin and Its Therapeutic Targets. In: Mathias, C., McAleer, J., Szollosi, D. (eds) Pharmacology of Immunotherapeutic Drugs. Springer, Cham. https://doi.org/10.1007/978-3-030-19922-7_5

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