As the pathophysiology of psoriasis has become well elucidated, a plethora of targeted treatments have emerged that inhibit different components of immunologic pathways implicated. Notably, interleukin (IL)-17 is thought to be a downstream effector, and its interaction with its receptor (IL-17R) is thought to be a critical signaling hub and a desirable target for inhibition.2 Currently, there is only one inhibitor of IL-17RA – brodalumab.
Brodalumab is a fully human monoclonal antibody of specifically the IL-17RA subunit of the receptor complex.3 It has been successful in achieving significant clearance as monotherapy in patients with moderate-to-severe plaque psoriasis. It also demonstrates efficacy in tough-to-treat areas such as the nails, scalp, palms, and soles.4 Furthermore, recent studies have demonstrated additional utility in patients who have failed to achieve response with IL-17A inhibitors such as secukinumab and ixekizumab. Lastly, cost-effectiveness studies have determined brodalumab to be the most economical biologic for the treatment of moderate-to-severe plaque psoriasis in the United States.5 This review will expand upon these details.
IL-17 Axis in Psoriasis
While numerous cytokines and chemokines have been implicated in the pathogenesis of psoriasis, the IL-23/IL-17 axis is a critical hub (Figure 1).6,7 Interleukin-17 (IL-17) is a pro-inflammatory cytokine that is produced by a variety of immune cells, including T helper 17 (Th17) cells, gamma/delta T cells, and innate lymphoid cells. IL-17 promotes the recruitment and activation of immune cells in the skin, leading to the production of additional cytokines and chemokines, which contribute to the inflammation and tissue damage seen in psoriasis. Importantly, IL-23 plays a pivotal role in IL-17 secretion and acts upstream by inducing Th17 cells.8
IL-17 exerts its effects by binding to a receptor complex composed of IL-17RA and IL-17RC, which is expressed on a variety of cells, including keratinocytes, fibroblasts, and immune cells.9 In addition, the IL-17 cytokine family consists of 6 isoforms (IL-17A-F), which may exert differential effects.10 Upon binding to the receptor complex, IL-17 activates a signaling cascade that leads to the activation of transcription factors, such as nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1). These transcription factors drive the expression of pro-inflammatory genes, such as IL-6, IL-8, and tumor necrosis factor alpha (TNF-α), which contribute to the development and maintenance of psoriatic lesions.
The importance of IL-17 in the pathogenesis of psoriasis is supported by several lines of evidence.11 First, IL-17 is elevated in the serum and skin lesions of patients with psoriasis. Second, genetic studies have identified variants in genes related to the IL-17 pathway that are associated with an increased risk of psoriasis. Finally, therapies targeting the IL-17 pathway have shown significant efficacy in treating psoriasis.
Current Therapeutics Targeting IL-17 Axis
