Baseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab

doi:10.1016/j.jaci.2018.07.028

Journal of Allergy and Clinical Immunology

Volume 143, Issue 1, January 2019, Pages 142-154

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https://doi.org/10.1016/j.jaci.2018.07.028 Get rights and content

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.

Section snippets

Study patients and skin samples

Skin biopsy specimens were obtained from adults with moderate-to-severe chronic AD in a randomized, placebo-controlled, multicenter, phase 2a clinical trial (NCT01941537) of IL-22 blockade with the mAb fezakinumab (ILV-094).²⁷ Patients were randomized 2:1 to either intravenous drug (n = 40) or placebo (n = 20), with a loading drug dose of 600 mg at baseline (day 0), followed by 300 mg at weeks 2, 4, 6, 8, and 10 (last dose).

Lesional and nonlesional biopsy specimens were obtained before

Study population

As recently reported, clinical scores (SCORAD, Investigator Global Assessment, and body surface area scores) significantly improved in patients with severe AD (baseline SCORAD score ≥ 50) starting at 6 to 8 weeks of IL-22 antagonism (administered intravenously every other week between 0 and 10 weeks), with progressive improvements for another 10 weeks after the last dose until end of study (week 20) compared with placebo.²⁷ Baseline patients' characteristics are shown in Table I.

Improvement of the AD transcriptome

We performed

Discussion

IL-22–producing cells have been suggested to be pathogenically linked to AD, with increased IL-22 expression in both skin and blood compartments.11, 12 Increased IL-22 levels have also been shown in patients with other inflammatory diseases, including psoriasis, inflammatory bowel diseases, and rheumatoid arthritis.¹⁵ In patients with Crohn disease, greater baseline serum IL-22 levels were associated with greater likelihood of an anti–IL-23 therapeutic response.⁵⁸

Our study is the first to

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: 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.

^∗: These authors contributed equally to this work.

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Atopic dermatitis and inflammatory skin diseaseBaseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab

Background

Objective

Methods

Results

Conclusions

Section snippets

Study patients and skin samples

Study population

Improvement of the AD transcriptome

Discussion

Lancet

Dermatol Clin

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Invest Dermatol

Structure

Immunity

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Invest Dermatol

J Invest Dermatol

J Dermatol Sci

Allergol Int

Cytokine

Am J Hum Genet

J Invest Dermatol

Curr Opin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Immunol Allergy Clin North Am

J Allergy Clin Immunol

J Am Acad Dermatol

J Invest Dermatol

J Allergy Clin Immunol

Dermatol Clin

J Invest Dermatol

J Invest Dermatol

J Allergy Clin Immunol

Biochim Biophys Acta

New insights into the epidemiology of childhood atopic dermatitis

Allergy

Dupilumab treatment in adults with moderate-to-severe atopic dermatitis

N Engl J Med

Two phase 3 trials of dupilumab versus placebo in atopic dermatitis

N Engl J Med

A new class of biologic agents facing the therapeutic paradigm in psoriasis: anti-IL-23 agents

Expert Opin Biol Ther

Atopic dermatitis and inflammatory skin disease
Baseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab