Baseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab - 17/09/18

Doi : 10.1016/j.jaci.2018.07.028

Patrick M. Brunner, MD, MSc ^a,^{∗
These authors contributed equally to this work.}, Ana B. Pavel, PhD ^b,^{∗
These authors contributed equally to this work.}, Saakshi Khattri, MD ^b, Alexandra Leonard, BA ^b, Kunal Malik, MD ^b, Sharon Rose, MD ^b, Shelbi Jim On, MD ^b, Anjali S. Vekaria, MD ^b, Claudia Traidl-Hoffmann, MD ^c,^d, Giselle K. Singer, BS ^b, Danielle Baum, RN ^b, Patricia Gilleaudeau, RN, MSN, FNP ^a, Mary Sullivan-Whalen, RN, MSN, FNP ^a, Judilyn Fuentes-Duculan, MD ^a, Xuan Li, BSc ^a, Xiuzhong Zheng, MSc ^a, Yeriel Estrada, BS ^b, Sandra Garcet, PhD ^a, Huei-Chi Wen, MD, PhD ^b, Juana Gonzalez, PhD ^a, Israel Coats, BA ^a, Inna Cueto, MSc ^a, Avidan U. Neumann, PhD ^c, Mark G. Lebwohl, MD ^b, James G. Krueger, MD, PhD ^a, Emma Guttman-Yassky, MD, PhD ^a,^b,^⁎
^a Laboratory for Investigative Dermatology, Rockefeller University, New York, NY
^b Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY
^c Institute of Environmental Medicine, University Center for Health Sciences at the Klinikum Augsburg, Technical University Munich and Helmholtz Zentrum München−German Research Center for Environmental Health, Augsburg, Germany
^d Christine Kühne−Center for Allergy Research and Education (CK-CARE), Davos, Switzerland

^∗Corresponding author: Emma Guttman-Yassky, MD, PhD, Department of Dermatology, Icahn School of Medicine at Mount Sinai, 5 E 98th St, New York, NY 10029.Department of DermatologyIcahn School of Medicine at Mount Sinai5 E 98th StNew YorkNY10029

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Abstract

Background

IL-22 is potentially a pathogenic cytokine in patients with atopic dermatitis (AD), but the molecular effects of IL-22 antagonism have not been defined in human subjects.

Objective

We sought to evaluate the cellular and molecular effects of IL-22 blockade in tissues from patients with moderate-to-severe AD.

Methods

We assessed lesional and nonlesional skin from 59 patients with moderate-to-severe AD treated with anti–IL-22 (fezakinumab) versus placebo (2:1) using transcriptomic and immunohistochemistry analyses.

Results

Greater reversal of the AD genomic profile was seen with fezakinumab versus placebo, namely 25.3% versus 10.5% at 4 weeks (P = 1.7 × 10⁻⁵) and 65.5% versus 13.9% at 12 weeks (P = 9.5 × 10⁻¹⁹), respectively. Because IL-22 blockade showed clinical efficacy only in patients with severe AD, we used baseline median IL-22 mRNA expression to stratify for high (n = 30) and low (n = 29) IL-22 expression groups. Much stronger mean transcriptomic improvements were seen with fezakinumab in the IL-22–high drug-treated group (82.8% and 139.4% at 4 and 12 weeks, respectively) than in the respective IL-22–high placebo-treated group (39.6% and 56.3% at 4 and 12 weeks) or the IL-22–low groups. Significant downregulations of multiple immune pathways, including T_H1/CXCL9, T_H2/CCL18/CCL22, T_H17/CCL20/DEFB4A, and T_H22/IL22/S100A's, were restricted to the IL-22–high drug group (P < .05). Consistently, tissue predictors of clinical response were mostly genes involved in T-cell and dendritic cell activation and differentiation.

Conclusions

This is the first report showing a profound effect of IL-22 blockade on multiple inflammatory pathways in AD. These data, supported by robust effects in patients with high IL-22 baseline expression, suggest a central role for IL-22 in AD, indicating the need for a precision medicine approach for improving therapeutic outcomes in patients with AD.

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Key words : Atopic dermatitis, moderate-to-severe patients, IL-22, fezakinumab, precision medicine, immune, cytokines, treatment

Abbreviations used : AD, AUC, DC, DEG, FCH, FDR, IL-22R, LCE, MADAD

Plan

Methods

Study patients and skin samples

Immunohistochemistry

Quantitative RT-PCR and microarray analysis

Statistical analyses

Results

Study population

Improvement of the AD transcriptome

Fezakinumab effects depend on high baseline IL-22 expression

Fezakinumab broadly decreases immune activation in skin

Modulation of immune and barrier responses with fezakinumab measured by using RT-PCR and immunohistochemistry

Predictor of fezakinumab treatment response

Effects on gene signatures

Discussion

Supported by National Institutes of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grant no. 1UM1AR063917. P.M.B. was supported in part by grant no. UL1 TR0001866 from the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program. Fezakinumab was provided by Pfizer (New York, NY).

Disclosure of potential conflict of interest: P.M.B. is an employee of the Rockefeller University and has received personal fees from LEO Pharma, Sanofi Genzyme, and Pfizer. C.T.-H. is an employee of the Technical University Munich and the Helmholtz Zentrum München and has received research support from Danone Nutricia and personal fees from Novartis and La Roche Posay. M.G.L. is an employee of Mount Sinai, which receives research funds from Abbvie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen/Johnson & Johnson, Kadmon, Medimmune/Astra Zeneca, Novartis, Pfizer, Valeant, and ViDac, and is also a consultant for Allergan, Aqua, LEO Pharma, and Promius. J.G.K. is an employee of the Rockefeller University and has received research support (grants paid to his institution) and/or personal fees from Pfizer, Amgen, Janssen, Lilly, Merck, Novartis, Kadmon, Dermira, Boehringer, Innovaderm, Kyowa, BMS, Serono, BiogenIdec, Delenex, AbbVie, Sanofi, Baxter, Paraxel, Xenoport, and Kineta. E.G.-Y. is an employee of Mount Sinai and has received research funds (grants paid to the institution) from Abbvie, Celgene, Eli Lilly, Janssen, MedImmune/Astra Zeneca, Novartis, Pfizer, Regeneron, Vitae, Glenmark, Galderma, Asana, Innovaderm, Dermira, and UCB and is also a consultant for Sanofi Aventis, Regeneron, Stiefel/GlaxoSmithKline, MedImmune, Celgene, Anacor, AnaptysBio, Dermira, Galderma, Glenmark, Novartis, Pfizer, Vitae, LEO Pharma, Abbvie, Eli Lilly, Kyowa, Mitsubishi Tanabe, Asana Biosciences, and Promius. The rest of the authors declare that they have no relevant conflicts of interest.