Topical Agents and Emerging Perspectives in Psoriasis
Topical Agents and Emerging Perspectives in Psoriasis
Psoriasis is a chronic inflammatory skin disease that affects approximately 2–3% of the Caucasian population. Red and scaly plaques, usually localized at the scalp, elbows, knees and buttocks, characterize the most common form of psoriasis, so-called 'plaque-type psoriasis'. Histologically, it is featured by a marked thickening of the epidermis and cutaneous infiltration of inflammatory cells, and by an increase in the number of dilated blood vessels in the upper dermis. The differentiation of keratinocytes is extensively altered in psoriasis: the maturation of keratinocytes from the basal layer to the cornified layer, which in normal skin lasts for approximately 28 days, is shortened to 5 days. This shortened maturation is associated with an evident reduction of the granular layer, with an aberrant terminal differentiation of keratinocytes, which is mainly reflected by parakeratosis.
Initially, it was believed that the pathogenic mechanism exclusively involved keratinocytes. However, several observations supported the view that T cells played a key role in the pathogenesis of psoriasis and, in particular, Th1 cells, producing IFN-γ, TNF-α and IL-2, were thought to be the specific T-cell subset involved in psoriatic lesion formation. Recently, a new subset of effector CD4 T cells, known as Th17 cells, has been discovered to be involved in psoriasis pathogenesis. Th17 cells are developmentally and functionally distinct from Th1 and Th2 cells, and they are defined by their ability to synthesize IL-17A, IL-17F and IL-22. The differentiation, proliferation and survival of Th17 are dependent on IL-6, TGF, IL-1β, IL-23 and IL-21. In particular, IL-23 is crucial for Th17 maintenance and to drive expansion and pathogenicity at later stages of Th17 development. Structurally, IL-23 is similar to IL-12 because they share a common p40 subunit that is covalently linked to either a p35 or p19 subunit to form IL-12 or IL-23, respectively. Activated myeloid dendritic cells secrete IL-23, driving T-cell differentiation toward Th17 subset, and also release IL-12, inducing Th1 differentiation.
Conventional treatments act as nonspecific immunomodulants that broadly suppress the inflammatory response characterizing the psoriatic plaque formation. Their efficacy is variable and associated with organ-specific toxicity. Instead, available biologic agents, as well as new topical drugs, target key cytokines or specific inflammatory pathways determining a highly selective suppression of the immune activation.
Psoriasis severity is the most important parameter that drives the choice of treatment, and it is measured by a well-established index, called the Psoriasis Area and Severity Index (PASI). It is also commonly used in clinical trials to evaluate the therapeutic response to systemic treatments, together with the physician's global assessment (PGA).
However, PASI is seldom used to measure the efficacy of topical products, as it is not very sensitive in patients with less than 5–10% body surface area (BSA) or in those patients who had a PASI <3.
An effective and standardized approach that measures the therapeutic response of small levels of psoriasis is needed. Some assessment tools have been recently introduced for measuring mild or circumscribed psoriasis, including overall lesion assessment and target lesion severity scores. This latter evaluates scale, infiltration and erythema of a single lesion that is considered a target for assessing the response to treatment. As suggested by Feldman et al., it might be effectively used in clinical trials and, if necessary, it might be supported by PGA and quality-of-life measures.
Another tool that could be proven valuable as responder index is the National Psoriasis Foundation Psoriasis Score.
Other factors, including comorbidities, need to be considered for selecting the optimal therapeutic strategy. Indeed, growing evidence has shown an association with an increased risk of cardiovascular mortality, the metabolic syndrome, obesity and Type 2 diabetes compared with the general population, leading to a new concept of psoriasis as systemic disease. Moreover, patients with psoriasis have a higher risk of developing depression or anxiety, affecting social, occupational, sexual and financial aspects of their life and even causing them to experience suicidal feelings.
Patients are often dissatisfied with current therapeutic approaches, and their compliance to treatment is poor. Therefore, the management of psoriasis is challenging.
Psoriasis as a Complex Immune-mediated Disorder
Psoriasis is a chronic inflammatory skin disease that affects approximately 2–3% of the Caucasian population. Red and scaly plaques, usually localized at the scalp, elbows, knees and buttocks, characterize the most common form of psoriasis, so-called 'plaque-type psoriasis'. Histologically, it is featured by a marked thickening of the epidermis and cutaneous infiltration of inflammatory cells, and by an increase in the number of dilated blood vessels in the upper dermis. The differentiation of keratinocytes is extensively altered in psoriasis: the maturation of keratinocytes from the basal layer to the cornified layer, which in normal skin lasts for approximately 28 days, is shortened to 5 days. This shortened maturation is associated with an evident reduction of the granular layer, with an aberrant terminal differentiation of keratinocytes, which is mainly reflected by parakeratosis.
Initially, it was believed that the pathogenic mechanism exclusively involved keratinocytes. However, several observations supported the view that T cells played a key role in the pathogenesis of psoriasis and, in particular, Th1 cells, producing IFN-γ, TNF-α and IL-2, were thought to be the specific T-cell subset involved in psoriatic lesion formation. Recently, a new subset of effector CD4 T cells, known as Th17 cells, has been discovered to be involved in psoriasis pathogenesis. Th17 cells are developmentally and functionally distinct from Th1 and Th2 cells, and they are defined by their ability to synthesize IL-17A, IL-17F and IL-22. The differentiation, proliferation and survival of Th17 are dependent on IL-6, TGF, IL-1β, IL-23 and IL-21. In particular, IL-23 is crucial for Th17 maintenance and to drive expansion and pathogenicity at later stages of Th17 development. Structurally, IL-23 is similar to IL-12 because they share a common p40 subunit that is covalently linked to either a p35 or p19 subunit to form IL-12 or IL-23, respectively. Activated myeloid dendritic cells secrete IL-23, driving T-cell differentiation toward Th17 subset, and also release IL-12, inducing Th1 differentiation.
Conventional treatments act as nonspecific immunomodulants that broadly suppress the inflammatory response characterizing the psoriatic plaque formation. Their efficacy is variable and associated with organ-specific toxicity. Instead, available biologic agents, as well as new topical drugs, target key cytokines or specific inflammatory pathways determining a highly selective suppression of the immune activation.
Psoriasis severity is the most important parameter that drives the choice of treatment, and it is measured by a well-established index, called the Psoriasis Area and Severity Index (PASI). It is also commonly used in clinical trials to evaluate the therapeutic response to systemic treatments, together with the physician's global assessment (PGA).
However, PASI is seldom used to measure the efficacy of topical products, as it is not very sensitive in patients with less than 5–10% body surface area (BSA) or in those patients who had a PASI <3.
An effective and standardized approach that measures the therapeutic response of small levels of psoriasis is needed. Some assessment tools have been recently introduced for measuring mild or circumscribed psoriasis, including overall lesion assessment and target lesion severity scores. This latter evaluates scale, infiltration and erythema of a single lesion that is considered a target for assessing the response to treatment. As suggested by Feldman et al., it might be effectively used in clinical trials and, if necessary, it might be supported by PGA and quality-of-life measures.
Another tool that could be proven valuable as responder index is the National Psoriasis Foundation Psoriasis Score.
Other factors, including comorbidities, need to be considered for selecting the optimal therapeutic strategy. Indeed, growing evidence has shown an association with an increased risk of cardiovascular mortality, the metabolic syndrome, obesity and Type 2 diabetes compared with the general population, leading to a new concept of psoriasis as systemic disease. Moreover, patients with psoriasis have a higher risk of developing depression or anxiety, affecting social, occupational, sexual and financial aspects of their life and even causing them to experience suicidal feelings.
Patients are often dissatisfied with current therapeutic approaches, and their compliance to treatment is poor. Therefore, the management of psoriasis is challenging.
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