Atopic dermatitis and skin disease
IL-17A is essential for cell activation and inflammatory gene circuits in subjects with psoriasis

https://doi.org/10.1016/j.jaci.2012.04.024Get rights and content

Background

In subjects with psoriasis, inflammation and epidermal hyperplasia are thought to be controlled by T cell–derived cytokines. Evidence suggests that the TH17 cell cytokine IL-17A (IL-17) might play a role in disease pathogenesis.

Objective

We sought to understand the effect that neutralization of IL-17 has on the clinical features of psoriasis and to understand the role that IL-17 has in inflammatory pathways underlying psoriasis in human subjects.

Methods

We examined skin lesions obtained from 40 subjects participating in a phase I, randomized, double-blind, placebo-controlled trial of the anti–IL-17 mAb ixekizumab (previously LY2439821) in which subjects received 5, 15, 50, or 150 mg of subcutaneous ixekizumab or placebo at weeks 0, 2, and 4.

Results

There were significant dose-dependent reductions from baseline in keratinocyte proliferation, hyperplasia, epidermal thickness, infiltration into the dermis and epidermis by T cells and dendritic cells, and keratinocyte expression of innate defense peptides at 2 weeks. By week 6, the skin appeared normal. Quantitative RT-PCR and microarrays revealed an ablation of the disease-defining mRNA expression profile by 2 weeks after the first dose of study drug. The effect of IL-17 blockade on expression of genes synergistically regulated by IL-17 and TNF-α was of higher magnitude at 2 weeks than in prior studies with TNF-α antagonism.

Conclusion

Our data suggest that IL-17 is a key “driver” cytokine that activates pathogenic inflammation in subjects with psoriasis. Neutralizing IL-17 with ixekizumab might be a successful therapeutic strategy in psoriasis.

Section snippets

Study design and subjects

A total of 46 subjects with chronic moderate-to-severe plaque psoriasis participated in a phase I, randomized, subject- and investigator-blinded, placebo-controlled, dose-escalation study of ixekizumab, an anti–IL-17 mAb. Subjects were randomized to groups receiving subcutaneous injections of 5 mg (n = 8), 15 mg (n = 8), 50 mg (n = 8), or 150 mg (n = 8) of ixekizumab or placebo (n = 8) or to groups receiving intravenous infusions of 15 mg (n = 5) of ixekizumab or placebo (n = 1; intravenous

Results

Ixekizumab was administered to 32 subjects with plaque psoriasis by means of subcutaneous injection across a range of doses from 5 to 150 mg at weeks 0, 2, and 4. Eight subjects received placebo injections at the same time points. Baseline characteristics for these patients are presented in Table E1. Skin biopsies for IL-17 pathway and other disease-related biomarkers and histopathology were performed before treatment (baseline) and again at weeks 2 and 6 after starting the study drug.

Discussion

Although autoimmune inflammation was long considered to be driven by TH1 T-cell activation and associated cytokines (ie, IFN-γ), the discovery of TH17 T cells and the causality of TH17 T cells in inducing experimental autoimmune encephalitis greatly altered this concept.44, 45, 46

In turn, this then raised the question of whether TH17 T cells have an important pathogenic contribution in human immune-mediated inflammatory diseases. Psoriasis vulgaris is a strong candidate disease for pathogenic

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    Supported by Eli Lilly and Company.

    Disclosure of potential conflict of interest: J. G. Krueger is a consultant for Centocor/Janssen, Pfizer, Boehringer-Ingelheim, and Merck and has received research support from Amgen, Novartis, Eli Lilly, and Merck. P. A. Haslett is a former employee of Eli Lilly and Company. K. M. Phipps, J. McColm, and R. W. Hoffman hold stock in Eli Lilly and Company. G. S. Cameron is employed by Eli Lilly and Company. S. Banerjee is an employee of and holds stock in Eli Lilly and Company. The rest of the authors declare that they have no relevant conflicts of interest.

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