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Pathophysiology


have shown that IL-21 can enhance the expression of Th1-associated transcription factors, so increasing IFN-γ production, and could also make T cells resistant to the suppressive effects of regulatory T cells.18


The lesional skin of psoriatic patients also contains high levels of IL-23, a heterodimeric cytokine composed of IL-23p19 and IL12/IL-23p40 subunits, and this cytokine produced mostly by myeloid dendritic cells is able to expand and maintain Th17 cell responses.19 Moreover, IFN-γ stimulates the production of IL23 by mDC.20 Notably, intradermal administration of IL-23 in mice induces skin alterations very similar to those observed in psoriasis, through a process that is largely mediated by endogenous TNF-a and IL-22 and dependent on chemokine/ chemokine receptor interactions. In addition, IL-23 increases its own receptor expression on activated naïve T cells leading to an amplification loop.21 Th17 cytokines, and also IFN-γ, increase the expression chemokine ligand CCL20 in keratinocytes, which is a chemoattractant for CCR6-expressing dendritic and T cells, providing a positive chemotactic feedback loop leading to the accumulation of these pathogenic cells.22


Th17-related cytokines enhance the synthesis of IL-20 by DCs and proliferating keratinocytes. IL-20 is highly produced in psoriasis, and its over-expression in transgenic mice causes epidermal thickening. Interestingly, the skin alterations in IL-20-transgenic mice occur without immune cell infiltration, thus suggesting that IL-20 is a downstream mediator in the psoriasis-associated immune- inflammatory cascade.23


Another cytokine involved in the pathogenesis of psoriasis is IL-22, which is produced by Th22 and Th17 cells. High concentrations of IL-22 have been reported in patients with psoriasis24


and


IL-22 triggers the production of antimicrobial peptides and expression of genes involved in epidermal differentiation and survival. IL-22 induces keratinocyte hyperplasia and acanthosis.


Moreover, Th22 expresses the chemokine receptors, CCR10, CCR6 and CCR4. CCR6 is the receptor for CCL20, which is overexpressed in psoriatic keratinocytes.25 TNF-a potently induces diverse


chemokines, enhances the expression of IL-22 receptor pathway elements, and amplified some of the effects of IL-22.20 Another subset of CD4+ T cells, which expresses constitutively high levels of CD25 (the IL-2 receptor chain), the transcription factor FoxP3, and the co-stimulation molecule CTLA-4, suppress the activity of other T cells by production of inhibitory cytokines such as IL-10 and TGF-b. These are called T-regulatory (Treg) cells and are able to protect against autoimmune reaction and lead to resolution of inflammation. In psoriasis, Treg has a deficient regulatory activity and, moreover, effector T cells were resistant to their suppression activity.26


This could be


mediated by high levels of IL-21, which are able to counteract T-reg suppressive activity on effector T cells.18


Biologics and the role of IL-17 The main goal of psoriasis treatment is to clear skin lesions and improve health-related quality of life in a sustained manner. This can be achieved, albeit with limitations, with topical agents with very broad effects such as corticosteroids, and vitamin D and its analogues, as well as phototherapy with UV light in mild cases. In more severely affected patients, phototherapy and systemic immunosuppressant agents are recommended, either alone or in combination. Biologic agents targeting specific components of the immune system (cells or cytokines) have recently emerged as a therapeutic option for patients with moderate and severe psoriatic disease.27


Biologics used to treat psoriasis


specifically block the action of T cells or act as inhibitors of inflammatory mediators such as TNF and ILs. Substantial contributions to the understanding of the disease have been made by studying essential components of the inflammation process, ultimately leading to the development of biologics such as adalimumab and etanercept, which are TNF antagonists, and ustekinumab, a monoclonal antibody that targets both IL-12 and -23 (p40 subunit). However, the prolonged use of these agents results in high treatment costs and may present limiting toxicities.27,28


Hence, the search


for highly specific biologic agents that mitigate the problem of broad adverse effects is far from being over. A growing body of evidence points to IL-17 as a key player in the pathogenesis of psoriasis and


other autoimmune diseases with potential to reduce the safety risks associated with currently approved agents.


Role of IL-17 in psoriasis pathophysiology The IL-17 family comprises six cytokines (A–F) and five receptors (A–E). The most relevant member of the family is IL-17A – the 'effector cytokine' in the pathophysiology of psoriasis – which is produced by differentiated Th17 cells, and IL-17A is detected at high levels in psoriatic lesions. Moreover, serum levels of IL-17 appear to be associated with the severity of tissue lesions. Other IL-17- producing cells (for example, mast cells and neutrophils) are also present at higher densities in skin lesions and seem to be the first producers of IL-17 at the onset of psoriatic plaque.29,30 Upon stimulation of receptors for


IL-23 present at the surface of Th17 cells, IL-17A expression is upregulated, resulting in the induction of other cytokines such as IL-21 and IL-22, which promote keratinocyte proliferation. In conjunction with IL-22, IL-17A triggers an innate immune response through the expression of molecules necessary for neutrophil recruitment. IL-17A promotes both Th17 cell and neutrophil recruitment through upregulation of chemokines by hyperproliferating keratinocytes in psoriasis, and stimulates the production of antimicrobial peptides and IL-36 in these cells, which, together with IL-17A, promotes the expression of TNF-a. IL-17A also contributes to the disruption of the skin barrier by decreasing expression of cell adhesion factors and potentiates the inflammation process by acting, in a synergistic manner, with cytokines produced by other cells, including macrophages, fibroblasts and endothelial cells.29 This cross-talk between epidermal keratinocytes, cells of the immune system and other cell types is critical for maintaining the sustained state of inflammation characteristic of psoriasis and may partially explain the systemic nature of the disease. Psoriasis is associated with cardiovascular comorbidities, and patients with higher serum IL-17A serum levels present a higher risk of developing an adverse cardiovascular event such as stroke and myocardial infarction.30


Anti-IL-17 agents Secukinumab, a fully human mAb, is the www.hospitalpharmacyeurope.com 5


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