International Journal of Molecular Sciences Review Psoriasis Pathogenesis and Treatment AdrianaReview Rendon and Knut Schäkel * DepartmentPsoriasis of Dermatology, Pathogenesis Heidelberg University, and 69120 Treatment Heidelberg, Germany; [email protected] * Correspondence: [email protected] Adriana Rendon and Knut Schäkel * Received:Department 25 February of Dermatology, 2019; Accepted: Heidelberg 18 March University, 2019; Published:69120 Heidelberg, 23 March Germany 2019; [email protected] Abstract:* Correspondence:Research on [email protected] psoriasis pathogenesis has largely increased knowledge on skin biology in general.Received: In the 25 past February 15 years, 2019; Accepted: breakthroughs 18 March in2019 the; Published understanding: 23 March of2019 the pathogenesis of psoriasis have been translated into targeted and highly effective therapies providing fundamental insights into Abstract: Research on psoriasis pathogenesis has largely increased knowledge on skin biology in the pathogenesis of chronic inflammatory diseases with a dominant IL-23/Th17 axis. This review general. In the past 15 years, breakthroughs in the understanding of the pathogenesis of psoriasis discusses the mechanisms involved in the initiation and development of the disease, as well as have been translated into targeted and highly effective therapies providing fundamental insights the therapeuticinto the pathogenesisoptions that of have chronic arisen inflammatory from the dissection diseases with of the a inflammatorydominant IL-23 psoriatic/Th17 axis. pathways. This Our discussionreview discusses begins the by mechanisms addressing involved the inflammatory in the initiation pathways and development and key cellof the types disease, initiating as well and perpetuatingas the therapeutic psoriatic inflammation. options that have Next, arisen we from describe the thedissection role of of genetics, the inflammatory associated psoriatic epigenetic mechanisms,pathways. and Our the interactiondiscussion begins of the skinby addressing flora in the the pathophysiology inflammatory pathways of psoriasis. and Finally, key cell we types include a comprehensiveinitiating and review perpetuating of well-established psoriatic inflammation. widely available Next, we therapies describe the and role novel of genetics, targeted associated drugs. epigenetic mechanisms, and the interaction of the skin flora in the pathophysiology of psoriasis. Keywords:Finally,psoriasis; we include inflammation; a comprehensive chronic review skin of disease well-established widely available therapies and novel targeted drugs. Keywords: psoriasis; inflammation; chronic skin disease 1. Definition and Epidemiology Psoriasis is a chronic inflammatory skin disease with a strong genetic predisposition and autoimmune1. Definition pathogenic and Epidemiology traits. The worldwide prevalence is about 2%, but varies according to regions [1].Psoriasis It shows is aa lowerchronic prevalence inflammatory in Asian skin disease and some with African a strong populations, genetic predisposition and up to and 11% in Caucasianautoimmune and Scandinavian pathogenic populationstraits. The worldwide [2–5]. prevalence is about 2%, but varies according to regions [1]. It shows a lower prevalence in Asian and some African populations, and up to 11% in 1.1. ClinicalCaucasian Classification and Scandinavian populations [2–5]. The1.1. dermatologicClinical Classification manifestations of psoriasis are varied; psoriasis vulgaris is also called plaque-type psoriasis, and is the most prevalent type. The terms psoriasis and psoriasis vulgaris The dermatologic manifestations of psoriasis are varied; psoriasis vulgaris is also called plaque- are used interchangeably in the scientific literature; nonetheless, there are important distinctions typ among the different clinical subtypes (See Figure1). (A) (B) Figure 1. Cont. Int. J. Mol. Sci. 2019, 20, x; doi: FOR PEER REVIEW www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, 1475; doi:10.3390/ijms20061475 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, 1475 2 of 28 Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 2 of 28 (C) (D) (E) (F) FigureFigure 1. Clinical 1. Clinical manifestations manifestations of of psoriasis. psoriasis. (A,,B)) Psoriasis Psoriasis vulgaris vulgaris presents presents with with erythematous erythematous scalyscaly plaques plaques on on the the trunk trunk and and extensorextensor surfaces surfaces of ofthe the limbs. limbs. (C) Generalized (C) Generalized pustular pustular psoriasis. psoriasis. (D) (D) PustularPustular psoriasis localized localized to the to thesoles soles of the of feet. the This feet. variant This variant typically typically affects the affects palms theof the palms hands of the as well; hence, psoriasis pustulosa palmoplantaris. (E,F) Inverse psoriasis affects the folds of the skin hands as well; hence, psoriasis pustulosa palmoplantaris. (E,F) Inverse psoriasis affects the folds of the (i.e., axillary, intergluteal, inframammary, and genital involvement). skin (i.e., axillary, intergluteal, inframammary, and genital involvement). 1.2. Psoriasis1.2. Psoriasis Vulgaris Vulgaris About 90% of psoriasis cases correspond to chronic plaque-type psoriasis. The classical clinical About 90% of psoriasis cases correspond to chronic plaque-type psoriasis. The classical clinical manifestations are sharply demarcated, erythematous, pruritic plaques covered in silvery scales. The manifestationsplaques can arecoalesce sharply and cover demarcated, large areas erythematous, of skin. Common pruritic locations plaques include coveredthe trunk, in the silvery extensor scales. The plaquessurfaces of can the coalescelimbs, and and the scalp cover [6,7]. large areas of skin. Common locations include the trunk, the extensor surfaces of the limbs, and the scalp [6,7]. 1.3. Inverse Psoriasis 1.3. Inverse Psoriasis Also called flexural psoriasis, inverse psoriasis affects intertriginous locations, and is Alsocharacterized called flexural clinically psoriasis, by slightly inverse erosive psoriasis erythematous affects plaques intertriginous and patches. locations, and is characterized clinically by slightly erosive erythematous plaques and patches. 1.4. Guttate Psoriasis 1.4. GuttateGuttate Psoriasis psoriasis is a variant with an acute onset of small erythematous plaques. It usually affects Guttatechildren or psoriasis adolescents, is a and variant is often with triggered an acute by group-A onset of streptococcal small erythematous infections of plaques. tonsils. About It usually one-third of patients with guttate psoriasis will develop plaque psoriasis throughout their adult life affects children or adolescents, and is often triggered by group-A streptococcal infections of tonsils. [8,9]. About one-third of patients with guttate psoriasis will develop plaque psoriasis throughout their adult life [81.5.,9]. Pustular psoriasis 1.5. PustularPustular psoriasis psoriasis is characterized by multiple, coalescing sterile pustules. Pustular psoriasis can be localized or generalized. Two distinct localized phenotypes have been described: psoriasis Pustularpustulosa psoriasispalmoplantaris is characterized (PPP) and acrodermatitis by multiple, co coalescingntinua of Hallopeau. sterile pustules. Both of them Pustular affect psoriasis the can behands localized and feet; or PPP generalized. is restricted Two to the distinct palms and localized soles, and phenotypes ACS is more have distally been located described: at the psoriasistips pustulosa palmoplantaris (PPP) and acrodermatitis continua of Hallopeau. Both of them affect the hands and feet; PPP is restricted to the palms and soles, and ACS is more distally located at the tips of fingers and toes, and affects the nail apparatus. Generalized pustular psoriasis presents with an acute Int. J. Mol. Sci. Sci. 2019,, 20,, x 1475 FOR PEER REVIEW 3 of 28 of fingers and toes, and affects the nail apparatus. Generalized pustular psoriasis presents with an andacute rapidly and rapidly progressive progressive course course characterized characterized by diffuse by diffuse redness redness and subcorneal and subcorneal pustules, pustules, and is often and accompaniedis often accompanied by systemic by systemic symptoms symptoms [10]. [10]. Erythrodermic psoriasis is an acute condition in which over 90% of the total body surface is erythematous and inflamed.inflamed. Erythroderma can develop on any kind of psoriasis type, and requires emergency treatment (Figure(Figure2 2).). Figure 2. Erythrodermic psoriasis. 1.6. Comorbidities in Psoriasis Psoriasis typically affects the skin, but may also affect the joints, and hashas been associated with a number of diseases. Inflammation Inflammation is not limited to the psoriatic skin, and has been shown to affect different organ systems. Thus, it has been postulated that psoriasis is a systemic entity rather than a solely dermatologicaldermatological disease. disease. When When compared compared to control to control subjects, subjects, psoriasis psoriasis patients exhibitpatients increased exhibit hyperlipidemia,increased hyperlipidemia, hypertension, hypertension, coronary coronary artery disease, artery disease, type 2diabetes, type 2 diabetes, and increased and increased body massbody index.mass index. The metabolic The metabolic syndrome, syndrome, which which comprises comprises the aforementioned the aforementioned conditions conditions in a single in a patient, single