Psoriasis: Recent progress in molecular‐targeted therapies

Abstract

Psoriasis is a multifactorial recalcitrant inflammatory skin disease characterized by bothersome scaly reddish plaques especially on frequently chafed body parts, such as the extensor sites of the extremities and scalp. Nonetheless, through recent advance in molecular-targeted therapies including biologics and small-molecule inhibitors, even the severest symptoms of psoriasis and its comorbidities, such as psoriatic arthritis, can be excellently treated. The superb clinical effects lead to not only remarkable alleviation of symptoms but also a deep understanding of patients' impaired "quality of life" caused by this disease. Along with the development of novel treatment options targeting various specific molecules, such as proinflammatory cytokines and signal transduction-associated molecules, clinicians have thoroughly understood the molecular mechanism of psoriasis, and discovered that the IL-23/IL-17 axis mainly depending on Th17 cell function is a crucial pathogenesis of this disease. Accumulation of knowledge about the working mechanism and clinical effect of molecular-targeted therapies is indispensable for clinicians to establish a more refined therapeutic strategy for treating psoriasis.

Molecular Pathogenesis of Psoriasis and Biomarkers Reflecting Disease Activity

“…As shown by the remarkable efficacy of molecular-targeted therapies, the IL-23/IL-17 axis, which depends mainly on Th17-cell function, is considered the most essential mechanism of psoriasis ( Figure 1 ) [ 1 , 2 , 10 , 15 , 17 ]. Molecules regulated in the downstream of Th17 cytokines are identified as biomarker candidates ( Table 1 ).…”

“…These activated DCs release tumor necrosis factor (TNF) and IL-23 that synergistically propel the immune response process. TNF stimulates DCs in an autocrine manner but inhibits the function of pDCs [ 1 , 2 , 10 , 15 , 17 ]. A paradoxical reaction during treatment using TNF inhibitors can depend on pDC activation by cancelling TNF-mediated inhibition [ 21 ].…”

“…These factors play crucial roles in the formation of the psoriatic phenotype and the vicious inflammatory circle of a psoriatic lesion. While the role of IL-17 is broadly shared in other psoriatic diseases, such as PsA [ 15 ] and pustular psoriasis [ 46 ], the significance of IL-17 inhibition remains unclear in terms of treating palmoplantar pustulosis [ 47 , 48 ].…”

“…However, it plays a crucial role in tissue regeneration, wound healing, and host defenses, especially against fungal infections [ 98 , 99 , 100 ]. The signal can be transmitted via a pair of receptors (IL-10 and IL-22) through JAK/STAT pathways [ 15 , 99 , 100 ]. IL-22 upregulates the proliferation of epidermal keratinocytes and induces acanthosis of epidermis via STAT3 activation in inflammatory dermatoses, such as psoriasis and atopic dermatitis (AD) [ 101 , 102 ].…”

“…While severe psoriatic symptoms are often resistant to conventional treatment, recent advances in molecular-targeted therapies have enabled sufficient treatment and control in most cases. The clinical effects of these therapies allow for markedly reduced skin lesions, related symptoms, and comorbidities but also a deep understanding of the molecular mechanism of psoriatic diseases in which the interleukin (IL)-23/IL-17 axis based on Th17-cell-mediating cytokine network plays an essential role [ 11 , 15 ].…”