IL-23 Versus IL-17 in the Pathogenesis of Psoriasis: There Is More to the Story Than IL-17A

August 2019 | Volume 18 | Issue 8 | Supplement Individual Articles | 202 | Copyright © August 2019

April W. Armstrong MD MPH,ª Charlotte Read MBBS BSc,ª Craig L. Leonardi MD,b Leon H. Kircik MDc

aDepartment of Dermatology, University of Southern California Keck School of Medicine, Los Angeles, CA bSaint Louis University School of Medicine, Saint Louis, MO; Central Dermatology Saint Louis, MO cIcahn School of Medicine at Mount Sinai, NY; Indiana Medical Center, Indianapolis, IN; Physicians Skin Care, PLLC; Skin Sciences, PLLC; DermResearch, PLLC, Louisville, KY

These novel findings suggest that targeting IL-17A alone may be inadequate to control psoriasis, particularly in patients with severe and recalcitrant disease. Additionally, compared to patients who continued treatment with ustekinumab, patients who received brodalumab had superior rates of PASI-75 (72.6% vs 61.7%), PASI-90 (58.1% vs 25.2%), and PASI-100 (36.3% vs 5.4%).90 Proposed mechanisms to explain these findings of superiority of IL-17RA blockade (brodalumab) over IL12/23 blockade (ustekinumab) in psoriasis include incomplete suppression of IL-17 because IL-17 subtypes may still be expressed independent of TH17 cells. IL-17E in Psoriasis

Pathogenesis and Therapies That Target IL-17E
In psoriasis, the role of IL-17E is not understood. While some investigators have found IL-17E to have anti-inflammatory effects, others found IL-17E to have proinflammatory effects.16,57 The inflammatory effects of IL-17E may occur by activating macrophages to release inflammatory cytokines such as TNF-α and neutrophil chemokines.57 Evidence also suggests that IL-17E may be involved in the recruitment of innate immune cells.55,64

IL-17E signals via a heterodimeric receptor complex consisting of IL-17RA and IL-17RB and has a 16% homology with IL-17A.58,64 IL-17E is produced by both epithelial and immune cells.16 Epithelial cells that produce IL-17E derive from the lung, gastrointestinal tract, and uterus.16 Immune cells that produce IL-17E include intraepithelial lymphocytes, alveolar macrophages, eosinophils, NKT, and TH2 cells.16 Brodalumab is the only FDA-approved psoriasis therapy that targets IL-17E via IL- 17RA inhibition (Figure 2).81

CONCLUSION

In conclusion, psoriasis pathogenesis involves a complex interplay between IL-23 and IL-17, and both cytokines play crucial roles in psoriasis. IL-17 subtypes such as IL-17A, IL-17C, and IL-17F are abundant in psoriatic lesions. Furthermore, IL-17 subtypes can be produced by other non-TH17 cells. Thus, IL-17 produced by non-TH17 cells may contribute to pathogenesis of psoriasis and psoriatic arthritis. Therapies that target IL-23 and IL-17 have been shown to be effective in psoriasis. Importantly, aside from the therapeutic target, other factors such as binding affinity, dosing, and low immunogenicity profile may also play a key role in the efficacy of these psoriasis therapies.

DISCLOSURE

AWA has served as investigator or consultant to AbbVie, Janssen, Lilly, Leo, Novartis, UCB, Ortho Dermatologics, Dermira, Sanofi Genzyme, Regeneron, BMS, Dermavant, and Modernizing Medicine.

CLL served as a consultant/advisory board member for AbbVie, Amgen, Boehringer Ingelheim, Celgene Corporation, Dermira, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Leo Pharma A/S, Ortho Dermatologics, Pfizer, Inc., Sandoz (a Novartis Company), UCB, and Vitae; as a speaker for AbbVie, Amgen, Celgene Corporation, Eli Lilly and Company, Novartis, Sun Pharmaceuticals, Ltd., and UCB; as a principal investigator for Actavis, Amgen, Boehringer Ingelheim, Celgene Corporation, Cellceutix, Coherus Biosciences, Corrona, Dermira, Eli Lilly and Company, Galderma Laboratories, L.P., Glenmark Generics, Inc., Janssen Pharmaceuticals, Inc., Leo Pharma, Inc., Merck, Novartis, Novella, Pfizer, Inc., Sandoz (a Novartis Company), Sienna Biopharmaceuticals, Stiefel a GSK company, UCB, and Warner Chillcott.

LHK has been either an investigator, consultant, advisory board member, or a speaker for Amgen, Celgene, Ely Lilly, Novartis, OrthoDermatologics, Pfizer, SunPharma, and UCB.

CR has no conflicts to disclose.

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