Pathogenesis Psoriasis Update 2017 172c5x

2017 Update: Etiology and Pathogenesis of Psoriasis By Sara N. Fischer, PhD Reviewed by Alice B. Gottlieb, MD, PhD

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Psoriasis affects 1%-4% of the population worldwide, manifesting as chronic inflammation of the skin and characterized by scaly, erythematous patches, papules, and plaques, which are often pruritic. Immunopathogenesis involves interactions between the innate and adaptive immune systems. Advances in the understanding of the immunopathogenesis and genetics of psoriasis have established psoriasis as a chronic, immune-mediated systemic disease associated with significant morbidity and impaired quality of life.1Affecting 1% to 4% of the worldwide population, psoriasis is also linked with serious comorbid conditions, such as diabetes/metabolic syndrome, cardiovascular disease, and psoriatic arthritis (PsA).2,3 Increased understanding of the underlying immunopathogenesis and genetics of psoriasis has led to the development of several systemic therapies, many of which have been approved for the treatment of specific patient populations.1Therefore, it is important for clinicians to understand current data and clinical evidence regarding the pathogenesis of psoriasis and its related comorbidities. Clinical features and etiology of psoriasis Psoriasis is a multisystem disease predominately manifested as chronic inflammation of the skin and characterized by scaly, erythematous patches, papules, and plaques, which are often pruritic.4 As a chronic disease, psoriasis waxes and wanes throughout a patient's lifetime.4 The disease course is modified with initiation and cessation of treatment, and spontaneous remission is rare.4 Historically, psoriasis phenotypes have been based on morphologic classifications, but clinical findings may show overlap of several different categories in individual patients .4 The severity of psoriasis is defined by the extent of body surface involvement as well as the involvement of areas that substantially affect daily life, such as the hands, feet, face, and genital region.5 Approximately 80% of patients have mild to moderate disease and 20% have moderate to severe disease.5 Although the precise etiology of psoriasis remains unknown, a combination of immunologic, genetic, and environmental factors contribute to its development and exacerbation.4 Immunopathogenesis of psoriasis The immunopathogenesis of psoriasis involves interactions between the innate and adaptive immune systems, which lead to alterations in the epidermis and vasculature.5-11 Following an initial trigger, innate immunity danger signals activate plasmacytoid and CD11c+ dendritic cells, which

secrete cytokines such as interferon-alpha and tumor necrosis factor (TNF)-alpha, respectively.6,7 Early clinical studies of TNF inhibitors demonstrated the important role of this cytokine in driving psoriatic disease, prompting investigators to consider psoriasis to be primarily Th1response driven.6,12 However, recent reports indicate both Th17 cells and interferon-gammaproducing Th1 cells play essential roles in the pathogenesis of psoriasis.5,9,13In addition to its welldocumented proinflammatory properties, TNF-alpha signaling also promotes the generation and proliferation of Th17 cells.8 Th17 cell-mediated secretion of interleukin (IL)-17 and IL-22 results in keratinocyte proliferation, cytokine and chemokine secretion, and altered antimicrobial peptide production.5,7 In the skin, myeloid dendritic cells produce IL-12 and IL-23, which further induce the activation of Th1 and Th17 cells, respectively.6,9 A study of a murine arthritis model showed IL-23 induced spondyloarthropathy via actions on a specific population of entheseal T cells.10 These findings provide further evidence for the link between skin and t disease and suggest agents that target the IL-23 pathway may be effective for the treatment of these conditions.10 Other studies highlight the potential role of another Th17related cytokine, IL-36, in the pathogenesis of psoriasis.11,14 Taken together, continuous activation of the Th1 and Th17 pathways contribute to the chronic inflammatory phenotype observed in psoriasis patients.6 These findings have led to the development of systemic biologic therapies that target these pathways.7 Conclusion Psoriasis is characterized by scaly, erythematous patches, papules, and plaques, which are often pruritic. The pathogenesis of psoriasis involves the complex interplay of immunologic, genetic, and environmental factors. Taken together, current understanding of the underlying pathogenesis of psoriasis has given rise to the development of new therapeutic options for this complex disease. Published: 01/06/2017 References: 1. 2. 3. 4.

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Kurd SK, Gelfand JM. The prevalence of previously diagnosed and undiagnosed psoriasis in US adults: results from NHANES 2003-2004. J Am Acad Dermatol. 2009;60:218-224. Armstrong AW, Schupp C, Bebo B. Psoriasis comorbidities: results from the National Psoriasis Foundation surveys 2003 to 2011. Dermatology. 2012;225:121-126. Kimball AB, Glan D, Gelfand JM, et al. National Psoriasis Foundation clinical consensus on psoriasis comorbidities and recommendations for screening. J Am Acad Dermatol. 2008;58:1031-1042. Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008;58:826-850. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: case-based presentations and evidence-based conclusions. J Am Acad Dermatol. 2011;65:137-174. Nestle FO, Di Meglio P, Qin JZ, et al. Skin immune sentinels in health and disease. Nat Rev Immunol. 2009;9:679-691. Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature. 2007;445:866-873. Johnson-Huang LM, McNutt NS, Krueger JG, et al. Cytokine-producing dendritic cells in the pathogenesis of inflammatory skin diseases. J Clin Immunol. 2009;29:247-256. Zaba LC, Fuentes-Duculan J, Eungdamrong NJ, et al. Psoriasis is characterized by accumulation of immunostimulatory and Th1/Th17 cell-polarizing myeloid dendritic cells. J Invest Dermatol. 2009;129:79-88. Sherlock JP, Joyce-Shaikh B, Turner SP, et al. IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4-CD8- entheseal resident T cells. Nat Med. 2012;18:1069-1076. Carrier Y, Ma HL, Ramon HE, et al. Inter-regulation of Th17 cytokines and the IL-36 cytokines in vitro and in vivo: implications in psoriasis pathogenesis. J Invest Dermatol. 2011;131:2428-2437. Chaudhari U, Romano P, Mulcahy LD, et al. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet. 2001;357:1842-1847. Lowes MA, Kikuchi T, Fuentes-Duculan J, et al. Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol. 2008;128:1207-1211. Marrakchi S, Guigue P, Renshaw BR, et al. Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med. 2011;365:620-628.