A review of emerging IL-17 inhibitors in the treatment of psoriasis focusing on preclinical through phase II studies

Abstract

Interleukin-17 has recently been identified as a key player in the pathogenesis of psoriasis. As such, several drugs targeting IL-17 are in various stages of clinical development. Areas covered: In this review, the authors describe several emerging therapies and drug candidates targeting IL-17. The authors detail many biologic injectable drug candidates as well as numerous potential oral and topical small molecule drug candidates. Expert opinion: Approval of IL-17 inhibitors has significantly improved the treatment options for psoriasis patients. Secukinumab and ixekizumab are approved in both Europe and the USA, and brodalumab is likely facing approval by the end of 2016. Numerous additional biologic and small molecule drug candidates are in the pipeline, and once deemed safe and effective will likely offer significant benefit to our psoriasis population.

Epigenetic control of IL-23 expression in keratinocytes is important for chronic skin inflammation

“…The TNF/IL-23/IL-17 cytokine cascade is suggested to be important for different inflammatory diseases. In psoriasis, inhibitors against these cytokines are already used in the therapy of this chronic skin inflammation 2 , 3 . Here we show in a mouse model that keratinocytes can produce IL-23 at levels sufficient to cause differentiation of IL-17A-producing T cells and skin inflammation.…”

“…Although the cause of psoriasis is unknown, development and maintenance of the disease occurs through the crosstalk between immune cells and keratinocytes. In particular, the interleukin (IL)-23/IL-17 axis and the tumor necrosis factor (TNF) pathway are of central importance in psoriasis as demonstrated by successful therapeutic intervention against these cytokines 2 , 3 . IL-23 is moreover increased in the skin of patients suffering from atopic dermatitis (AD) or alopecia areata 4 and in the serum of patients with autoimmune diseases as systemic lupus erythematosus (SLE) 5 or Crohn’s disease 6 .…”

Combined Transcriptomic Analysis Revealed AKR1B10 Played an Important Role in Psoriasis through the Dysregulated Lipid Pathway and Overproliferation of Keratinocyte

“…Currently, it is recognized that IL-23/17 dysregulation is involved in the immunopathology of psoriasis [ 10 ]. A sustained elevation of IL-23 can be found in the dendritic cells residing in the dermis, leading to Th-17 releasing IL-17 and IL-22, which further contribute to the overproliferation of keratinocytes [ 11 – 13 ]. Furthermore, continuous cytokines, chemokines, and antimicrobial peptides are released to chemoattract diverse immune cells, which amplify immune reaction, including the synthesis of CCL20, CXCL1, CXCL2, and CXCL8/IL-8 [ 14 – 16 ].…”

Short-term transcriptional response to IL-17 receptor-A antagonism in the treatment of psoriasis

“…1 Although older models of psoriasis pathogenesis focused on the role of T H 1 T cells in pathogenesis, the IL-23/T H 17 axis has recently gained more focus. 2 Cytokines belonging to the IL-17 cytokine family include IL-17A-F of which IL-17A, IL-17C, and IL-17F have shown elevated mRNA levels in lesional skin (LS) from patients with psoriasis. 3 The observed IL-17A, -17C, -17F-induced expression of proinflammatory target genes in keratinocytes (KCs) and other cell types 4,5 has led to the proposal that IL-17A, -17F, and -17C cytokines contribute to the ''feedforward'' loop, resulting from IL-17-induced release of inflammatory mediators, leading to the increased inflammation observed in patients with psoriasis.…”