Use of brodalumab for the treatment of psoriasis and psoriatic arthritis

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Date: Apr. 2015
From: Immunotherapy(Vol. 7, Issue 4)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 7,901 words
Lexile Measure: 1650L

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Author(s): Dario N Kivelevitch aff1 , Alan Menter [*] aff1

Keywords:

anti-IL-17; brodalumab efficacy; IL-17; monoclonal antibodies; psoriasis; psoriatic arthritis; safety; therapeutics

Psoriasis is a chronic immune mediated genetic disease affecting 2-3% of the population worldwide [1 ] (approximately 120 million people). Major advances in our understanding of its pathophysiology have led to new and more efficacious therapies over the past 20 years. An intricate network of cellular interactions underlies psoriasis immunopathogenesis, together with over 40 psoriasis-related genes. Different cellular subpopulations have been implicated in psoriasis onset and chronic inflammatory infiltrate. In recent years IL-23/Th17 axis suppression has proved to be a highly effective strategy in the treatment of psoriasis [ 2 ]. Brodalumab is a monoclonal antibody directed against the IL-17 receptor. This article will review the available current data on the immunopathogenesis of psoriasis, particularly relating to IL-17 and the efficacy and safety of brodalumab for the treatment of moderate-to-severe psoriasis and psoriatic arthritis (PsA).

IL-17 family

IL-17 comprises a unique cytokine family that includes six cytokines (IL-17A-IL-17F; Table 1) and five receptors (interleukins 17RA-17RE) [ 3,4 ] IL-17A and IL-17F are released as homodimers bound by a disulfide union. Additionally, monomeric IL-17A can combine with monomeric IL-17F forming the heterodimer IL-17A/IL-17F. IL-17A, IL-17F and IL-17A/IL-17F exert their effect on IL-17RA stimulating a receptor complex consisting of IL-17RA and IL-17RC subunits [3,5,6 ], IL-17C acts through an IL-17RA/RE complex [7 ]. IL-17A is the most potent of these cytokines, approximately 10-30-times greater than IL-17F; the heterodimer IL-17A/IL-17F has intermediate activity [8,9 ]. IL-17E (also known as IL-25) is involved in Th2 responses. The functions of IL-17B and IL-17 D remain incompletely understood [8 ].

Sources of IL-17

There is an intricate interplay of cells and cytokines in the pathogenesis and chronic inflammation in psoriasis with IL-17 being produced by different cellular subpopulations.

Th17 is a class of T-helper (Th) lymphocytes separate from the classic Th1 and Th2 T-cell subsets hitherto associated with psoriasis and eczema pathophysiology. The Th17 cellular subset is activated by IL-23 and is characterized by the expression of IL-17 A and F, IL-21 and IL-22. In human naive CD4+ T cells, ROR[gamma]t expression and conversion into Th17 were induced by IL-1[beta] and IL-6 from dendritic cells [11 ]. IL-23 is required for the survival but not differentiation of Th17 cells [ 12 ]. IL-23 is necessary for maintaining the Th17 phenotype, while IL-21 further amplifies Th17 differentiation [13 ]. Further exposure to IL-23 stimulates IL-17A production and expression of other Th17 cytokines, including IL-17F, IL-21 and IL22 [13 ].

Tc17 is a subset of CD8+ cells which similarly to Th17 require IL-23 and IL-21 for differentiation from naive CD8+ cells [14,15 ]. Tc17 cells have less cytotoxic activity compared with other CD8+ T cells [15 ]. However, Tc17 cells are found at high levels in the epidermis of psoriatic lesions and in smaller amounts in dermal psoriatic lesions [16 ].

V[gamma]9Vδ2 T cells are a novel proinflammatory subset of T cells that produce IL-17A and have been reported...

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Gale Document Number: GALE|A411322526