Targeting of interleukin-17 in the treatment of psoriasis

Abstract

“Psoriasis” is a chronic immune-mediated inflammatory disorder with epidermal hyperplasia. There is some evidence that the cytokine interleukin-17A (often known as IL-17), which is mainly produced by Th17 cells, has a role in the pathogenesis of psoriasis. “IL-17” is a pro-inflammatory cytokine mainly important in the host’s defense against extracellular bacteria and fungi. The three new therapies with biologic drugs – brodalumab, secukinumab, and ixekizumab – all target the IL-17 signaling pathway. Secukinumab and ixekizumab neutralize IL-17A, while brodalumab blocks its receptor. Results from clinical trials have shown marked improvements in disease severity in patients with moderate-to-severe plaque psoriasis, using any of these three drugs. The biologic agents were generally well tolerated, but the duration of the trials was relatively short. In this review, we focus on the role of the IL-17 cytokine family in the pathogenesis of psoriasis; the efficacy, safety, and tolerability of brodalumab, secukinumab, and ixekizumab in clinical trials; and possible differences between targeting of the IL-17A receptor and targeting of the IL-17A ligand.

Imiquimod-induced psoriasis-like skin inflammation is suppressed by BET bromodomain inhibitor in mice through RORC/IL-17A pathway modulation

“…We hypothesized that BET proteins are [17,19,[21][22][23]32]. Our study confirms these earlier observations.…”

“…This is confirmed by the efficacy of anti-IL23, -IL-17A and -IL-22 antibodies in mouse psoriasis-like skin inflammation models and anti-IL23/-IL-17A antibodies in human psoriatic patients [17,[20][21][22][23]. The IL-17A/IL-22 from both innate and adaptive immune cells mostly depends on RORC, as depicted by a lack of skin inflammation and the absence of IL-17A and IL-22 in RORC deficient mice treated with IMQ [18].…”

Safety of secukinumab in the treatment of psoriasis

“…Secukinumab is a fully human anti-IL-17A G1k monoclonal antibody that selectively targets and neutralizes IL-17A [3,7]. IL-17A is a pro-inflammatory cytokine produced primarily by Thelper 17 (Th17) cells, and it is also produced by natural killer cells, mast cells, and neutrophils [3].…”

“…IL-17A is a pro-inflammatory cytokine produced primarily by Thelper 17 (Th17) cells, and it is also produced by natural killer cells, mast cells, and neutrophils [3]. IL-17 circulates as a homodimer of 2 IL-17A chains or as a heterodimer of IL-17A and IL-17F [3]; both structures bind to the IL-17 cell surface receptor and initiate the NF-κB and cytosine-cytosine-adenosine-adenosine-thymidine enhancer binding protein transcription factor pathways, leading to inflammatory activity that has been linked to exacerbation of psoriasis [1,16]. By binding to circulating and tissue IL-17A, secukinumab inhibits its interaction with the IL-17A receptor, thereby inhibiting downstream release of pro-inflammatory cytokines and chemokines that contribute to the development of psoriasis [16,17].…”

“…Between 20% and 30% of patients with plaque psoriasis have moderate-tosevere forms that require systemic therapy [3]. The pathogenesis of psoriasis is not fully understood; however, critical T-cell subsets and effector cytokines that mediate chronic inflammation observed in psoriasis have been identified [2].…”