Journal of Clinical and Aesthetic Dermatology

Plaque-type Psoriasis Supplement 2016

An evidence-based, peer-reviewed journal for practicing clinicians in the field of dermatology

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A Novel Paradigm for Treatment of Moderate-to-severe Plaque-type Psoriasis [JUNE 2016 • VOLUME 9 • NUMBER 6 • SUPPLEMENT 1] SUPPLEMENT TO THE JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY S3 Introduction Psoriasis is a chronic inflammatory disease characterized by skin lesions and systemic inflammation. It is thought to be due to aberrant activation of the interleukin (IL)-23/T-helper (Th)17 immunologic pathway through a complex interplay between genetics and the environment. 1 Psoriasis is associated not only with physical morbidity, but also significant psychosocial impairment and a negative impact on quality of life. 2 Our understanding of the pathophysiology of psoriasis has greatly increased over the past few decades, in parallel with the development of new drugs to treat it. Prior to the 1980s, psoriasis was believed to be primarily a keratinocyte disorder, whereas, in the1980s, it was thought to be a disease primarily caused by general T cell activation. By the 1990s, the increasing importance of Th1 cells, IL-12, interferon gamma (IFNγ), and tumor necrosis alpha (TNFα) was noted. 3,4 Beginning around 2005, psoriasis was no longer considered a prototype Th1-mediated kin disease, but rather an IL-23/Th17 driven disease. 5 With greater knowledge of psoriasis' immunopathogenesis, new, rationally designed drugs have been brought to market, which raise the bar in efficacy and carry greater safety profiles than their predecessors. Structural and Immune Function In Healthy Skin Considered the body's largest organ, the skin provides a barrier between the harsh external environment and our internal organs. In fact, the skin serves several specific "barrier" functions. First, as a protective function, the stratum corneum maintains normal physiologic function for deeper skin layers. It acts as a sensor to barrier compromise, stimulating repair mechanisms. The skin also serves an antioxidant role, with endogenous molecules like superoxide dismutase that quell reactive oxygen species. In addition, the stratum corneum acts as a permeability barrier to water, maintaining skin hydration and preventing water loss into the environment. When water loss is detected, the skin releases stored precursor lipids from lamellar bodies to repair the mortar between the skin cell bricks, improving the barrier and reducing transepidermal water loss (TEWL) across the stratum corneum. 6 The skin plays a role in the body's immune system, with both circulating blood cells that migrate into the skin and resident cells playing independent roles. 7 In healthy skin, pro- inflammatory and balancing regulatory processes maintain homeostasis in response to external pathogens and during wound healing. In the case of psoriasis, there is an immune imbalance, with an overabundance of pro-inflammatory mediators and cells and a lack of regulation. In order to understand the immune defects that lead to psoriasis, one must have a basic knowledge of normal skin immune function, including the characteristics of immune cells themselves and their interactions. Keratinocytes. While best known as structural cells in the epidermis, keratinocytes are directly influenced by immune cell signals and play an important role themselves in inflammatory processes. Dendritic and T-cell cell derived cytokines stimulate activation and proliferation of keratinocytes. In the case of psoriasis, hyperproliferation with resulting abnormal cellular differentiation explain the clinical appearance of thick, scaly psoriatic plaques. Moreover, keratinocytes themselves produce pro- inflammatory cytokines that promote both antimicrobial peptide production and lead to dendritic cell and T-cell activation. 8,9 Neutrophils. Neutrophils are the most abundant type of white blood cells in the body. They are considered first- responders to sites of infection or other exposure during the acute phase of inflammation, where they initiate an initial immune attack. In cases of infection, neutrophils attack foreign organisms through degranulation and phagocytosis. Large accumulations of neutrophils clinically manifest as pus in the skin. In addition, neutrophils are involved in the initiation of psoriatic lesions, and they are histologically observed in the stratum corneum of psoriatic plaques as Munro's microabscesses and in the stratum spinosum as spongiform pustules of Kogoj. 10 Neutrophil activity is stimulated by IL-17A, and neutrophils release IL-17A and chemotactic factors themselves, which promote Th17 cell recruitment to skin. 11 Dendritic cells. Dendritic cells are immune cells that exist throughout the body. They process antigens and present them to other immune cells, hence their designation as antigen-presenting cells. Their interaction with both B- cells and T-cells result in activation with subsequent cytokine production. Once activated, mature dendritic cells migrate in The Role of IL-17 in the Pathogenesis and Treatment of Psoriasis a Joshua A. Zeichner, MD; b April Armstrong, MD a Icahn School of Medicine at Mount Sinai, New York, New York b University of Southern California, Los Angeles, California

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