Translating the science of psoriasis.
Knowledge about the pathophysiology of psoriasis has evolved substantially in recent years, since the identification of the T helper 17 (Th17) cells. Cytokines produced by these cells appear to play major roles in psoriatic inflammation. The cytokine interleukin (IL)-23 appears to promote regulatory T cells to differentiate into Th17 cells. Available and investigational therapies act on targets within these pathways.
IL-17; IL-23; Psoriasis treatment; Th17 pathway
As recently as 12 years ago, it was believed that psoriatic inflammation was driven by T helper 1 (Th1) cells. (1) More recent evidence elucidates the role of IL-23 and Th17 effector cytokines (eg, IL-17) in disease pathogenesis. (2,3) Many current and investigational therapies appear to act through these cytokines.
The tumor necrosis factor (TNF)-[alpha] inhibitor etanercept, for example, acts at least in part through its effect on Th17 cytokines. Evidence suggests that TNF-[alpha]-producing dendritic cells increase levels of IL-23, which in turn leads to Th17 cell proliferation and IL-17 and IL-22 induction. (2) Blocking TNF-[alpha] downregulates Th17 cytokines and the inflammatory products of dendritic cells, including IL-23.2 Clinical improvement has been correlated with early (ie, within 2 weeks of etanercept initiation) reduction in Th17 and dendritic cell products (eg, IL-23). Final disease resolution is associated with downregulation of Th1 cells. (2)
Normal human skin contains both Thl and Th17 cells. The former produce gamma interferon but not IL-17. The latter produce IL-17. Some, though not all, Th17 cells produce IL-22 as well as IL-17. (4) IL-17 upregulates expression of chemoattractants that are increased in psoriatic lesions, and appears to contribute to an influx of proinflammatory cells (eg, neutrophils). IL-22 appears to delay normal keratinocyte differentiation. (4)
IL-17 signaling targets both keratinocytes and dermal fibroblasts. IL-17 signaling to dermal fibroblasts promotes cellular infiltration, as well as increased accumulation of IL-17-producing cells in the skin. IL-17 signaling to keratinocytes contributes to hyperproliferation and attenuates differentiation. (5) These findings suggest that IL-17 plays an important role in both activating and maintaining inflammation in psoriasis.
At least six IL-17 cytokine isoforms (IL-17A through IL-17F) and five IL-17 receptors (IL-17RA through IL-17RE) have been identified. (6) Levels of IL-17A, IL-17C, and IL-17F are increased in psoriatic skin, suggesting that these proteins may play roles in the pathogenesis of psoriasis. (6) Secukinumab and ixekizumab, US Food and Drug Administration (FDA)-approved treatments for psoriasis, target IL-17A, and brodalumab, an investigational therapy, targets IL-17RA. (7-8)
IL-23 appears to induce differentiation of Foxp3+ regulatory T cells--which typically inhibit autoimmune responses--into proinflammatory Th17 cells. Evidence suggests that regulatory T-cell differentiation into Th17 cells leads to increased IL-17A production in psoriasis. These changes may perpetuate chronic autoimmune conditions. (3) Ustekinumab, an FDA-approved treatment for psoriasis, targets a protein subunit (p40) used by IL-23 and IL-12. (9)
Ustekinumab is administered once every 3 months. Yet its mean half-life is much shorter, ranging from roughly 2 weeks to 6.5 weeks (14.9 [+ or -] 4.6 days to 45.6 [+ or -] 80.2 days). (9) It is possible that ustekinumab exerts its prolonged benefit effect by promoting normalization of regulatory T cells.
The identification of Th17 cells and their role in psoriasis inflammation has greatly increased our understanding of the disease and the mechanisms of therapies. It also illuminates additional possible targets for new therapies.
(1.) Nickoloff BJ, Nestle FO. Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities. J Clin Invest. 2004; 113(12): 1664-1675.
(2.) Zaba LC, Cardinale I, Gilleaudeau P, et al. Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J. Exp. Med. 2007;204(13):3183-3194.
(3.) Bovenschen HJ, van de Kerkhof PC, van Erp PE, Woestenenk R, Joosten I, Koenen HJ. Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin. J Invest Dermatol. 2011; 131 (9): 1853-1860.
(4.) Nograles KE, Zaba LC, Guttman-Yassky E, et al. Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. Br J Dermatol. 2008; 159(5): 1092-1102.
(5.) Ha HL, Wang H, Pisitkun P, et al. IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms. Proc Natl Acad Sci USA. 2014;111(33):E3422-3431.
(6.) Johansen C, Usher PA, Kjellerup RB, Lundsgaard D, Iversen L, Kragballe K. Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin. Br J Dermatol. 2009; 160(2):319-324.
(7.) Cosentyx [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2016.
(8.) Martin DA, Towne JE, Kricorian G, et al. The emerging role of IL-17 in the pathogenesis of psoriasis: Preclinical and clinical findings. J Invest Dermatol. 2013; 133(1): 17-26.
(9.) Stelara [package insert]. Horsham, PA: Janssen Biotech Inc.; 2014.
Kenneth B. Gordon, MD, Professor of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Publication of this CME/CE article was jointly provided by Rutgers, The State University of New Jersey and Global Academy for Medical Education, LLC with Skin Disease Education Foundation (SDEF) and is supported by educational grants from AbbVie Inc. and Novartis Pharmaceuticals Corporation.
Dr Gordon has received an honorarium for his participation in this activity. He acknowledges the editorial assistance of Eileen McCaffrey, MS, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.
Kenneth B. Gordon, MD, Grant/Research: AbbVie Inc., Amgen Inc., Celgene Corporation, Eli Lilly and Company, and Janssen Pharmaceuticals, Inc. Consultant: AbbVie, Amgen, Boehringer Ingelheim Pharmaceuticals Inc, Celgene, Dermira Inc, Eli Lilly, Janssen, Novartis Pharmaceuticals Corporation, and Pfizer Inc.
Address reprint requests to: Kenneth B. Gordon, MD, 925 Sutton Drive, Northbrook, IL 60062; Gordon.firstname.lastname@example.org