Clinical and Molecular Effects of Interleukin-17 Pathway Blockade in Psoriasis
February 2020 | Volume 19 | Issue 2 | Original Article | 138 | Copyright © February 2020
Published online January 17, 2020
Lawrence Green MD,a Jeffrey M. Weinberg MD,b Alan Menter MD,c Jennifer Soung MD,d Edward Lain MD,e Abby Jacobsonf
aGeorge Washington University School of Medicine, Washington, DC bIcahn School of Medicine at Mount Sinai, New York, NY cBaylor Scott & White, Dallas, TX dSouthern California Dermatology, Santa Ana, CA eAustin Institute for Clinical Research, Pflugerville, TX fOrtho Dermatologics, Bridgewater, NJ
The interleukin-17 (IL-17) pathway plays a crucial role in the development of psoriasis. Briefly, naive T cells differentiate into helper T (Th17) cells through interaction with activated dendritic cells in the presence of IL-23, Th17 cells produce IL-17 cytokines, and keratinocytes stimulated by IL-17 ligands lead to aberrant differentiation and proliferation that promote production of proinflammatory chemokines and further recruitment of inflammatory cells, setting up a positive feedback loop. Currently, 3 US Food and Drug Administration–approved agents to treat psoriasis affect the IL-17 pathway: brodalumab, secukinumab, and ixekizumab. Brodalumab is a fully human IL-17 receptor A antagonist that blocks signaling of multiple downstream inflammatory cytokines involved in psoriasis. Secukinumab and ixekizumab selectively bind to and neutralize only IL-17A. Pharmacologic effects in patients with psoriasis include decreased keratinocyte hyperproliferation, reduced epidermal thickening, decreased inflammatory markers, and resolution of histologic and genomic features of psoriasis. In clinical trials, therapeutic doses of brodalumab, secukinumab, and ixekizumab have demonstrated skin clearance efficacy by psoriasis area and severity index and static physician’s global assessment scores at 12 weeks. The immunomodulation of these agents is associated with a favorable safety profile. Overall, the clinical improvement and normalization of genetic hallmarks of psoriasis provide a strong case for the unique role of IL-17 receptor blocking as a therapeutic mechanism of action to treat psoriasis. Understanding the unique mechanisms by which treatments interact with the IL-17 pathway to inhibit downstream proinflammatory signal cascade can help physicians make informed treatment decisions when selecting the appropriate medication for patients. J Drugs Dermatol. 2020;19(2)138-143 doi:10.36849/JDD.2020.4645
Psoriasis is a chronic, inflammatory, immune-mediated systemic disease with an estimated prevalence of 3.2% in the United States among individuals >20 years of age.1 It is characterized by abnormal proliferation of keratinocytes, increased dermal vascularity, and dermal infiltration of multiple inflammatory cells and by clinical presentation of erythema, induration, and scaling.2,3 Psoriasis has multiple symptoms with a substantial effect on both physical and emotional health-related quality of life, as well as a number of comorbid conditions.4-6
A complex series of immunologic events results in the formation of psoriatic plaques as well as the underlying systemic inflammation characteristic of psoriasis. Central to this process is the keratinocyte activation of dendritic cells. Inflammatory dendritic cells release interleukin-23 (IL-23) and IL-12 to activate helper T (Th17) cells, Th1 cells, and Th22 cells, which in turn produce psoriatic cytokines, including IL-17, tumor necrosis factor α (TNFα), and IL-22.7-9 The initial causes (environmental and/or genetic) that trigger the aberrant immune response and resulting cascade of immunologic events in psoriasis pathology are still not completely defined.
The current understanding of the complex pathophysiology associated with psoriasis has spurred the development of a variety of important new therapeutic agents that selectively target proinflammatory cytokines (eg, IL-17, IL-23, TNFα) rather than suppressing the immune system in its entirety, resulting in favorable efficacy and safety profiles compared with those of less-selective immunosuppressive agents.3 This review focuses on the central role of the IL-17 pathway in psoriasis pathophysiology and the clinical and molecular effects of the blockade of this pathway in the context of psoriasis treatment.
Overview of the Central Role of the IL-17 Pathway in Psoriasis
For many years, the Th1 pathway had been considered the primary driver in psoriasis.10 Research over the last decade,