Baseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab
Baseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab
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DOI：
10.1016/j.jaci.2018.07.028
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发表时间：
2019-01-01
影响因子：
14.2
通讯作者：
Guttman-Yassky, Emma
中科院分区：
文献类型：
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作者：
Brunner, Patrick M.;Pavel, Ana B.;Guttman-Yassky, Emma
背景：IL-22在特应性皮炎（AD）患者中是一种潜在的致病细胞因子，但IL-22拮抗剂在人类受试者中的分子效应尚未明确。目的：我们试图评估IL-22阻断在中重度AD患者组织中的细胞和分子效应。方法：我们使用转录组学和免疫组织化学分析评估了59例中重度AD患者的病变和非病变皮肤，这些患者接受了抗il -22 （fezakinumab）和安慰剂（2:1）的治疗。结果：fezakinumab与安慰剂相比，AD基因组谱的逆转更大，在4周时分别为25.3%和10.5% (P = 1.7 x 10(-5))，在12周时分别为65.5%和13.9% （P = 9.5 x 10(-19)）。由于IL-22阻断仅在严重AD患者中显示临床疗效，因此我们使用IL-22 mRNA的基线中位数表达来分层IL-22高表达组（n = 30）和低表达组（n = 29）。在高il -22药物治疗组（4周和12周分别为82.8%和139.4%）中，fezakinumab的平均转录组改善明显强于相应的高il -22安慰剂治疗组（4周和12周分别为39.6%和56.3%）或低il -22药物治疗组。高il -22药物组T(H)1/CXCL9、T(H)2/CCL18/CCL22、T(H)17/CCL20/DEFB4A、T(H)22/IL22/S100A等多条免疫通路的显著下调均局限于高il -22药物组(P
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 x 10(-5)) and 65.5% versus 13.9% at 12 weeks (P = 9.5 3 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(H)1/CXCL9, T(H)2/CCL18/CCL22, T(H)17/CCL20/DEFB4A, and T(H)22/IL22/S100A's, were restricted to the IL-22-high drug group (P