Department of Dermatology and Allergy, Charité - Universitätsmedizin, Berlin, Germany.
Translational Medicine, Novartis, Cambridge, Massachusetts.
Allergy. 2019 Jan;74(1):141-151. doi: 10.1111/all.13547. Epub 2018 Oct 15.
Omalizumab, a humanized recombinant monoclonal anti-IgE antibody, proved to be effective in patients with chronic spontaneous urticaria (CSU), including severe and treatment-refractory CSU. Here, we report omalizumab's effect on gene expression in skin biopsies from CSU patients enrolled in a double-blind, placebo-controlled study.
Chronic spontaneous urticaria patients (18-75 years) were randomized to either 300 mg omalizumab (n = 20) or placebo (n = 10) administered s.c. every 4 weeks for 12 weeks (NCT01599637). Lesional and nonlesional skin biopsies were collected from the same area of consenting patients and assessed at baseline and on Day 85 compared with skin biopsies from the same area of 10 untreated healthy volunteers (HVs). Gene expression data were generated using Affymetrix HG-U133Plus2.0 microarrays. Statistical analyses were performed using R packages.
At baseline, 63 transcripts were differentially expressed between lesional and nonlesional skin. Two-thirds of these lesional signatures were also differentially expressed between lesional and HV skin. Upon treatment with omalizumab, >75% of lesional signatures changed to reflect nonlesional skin expression levels (different vs placebo, P < 0.01). Transcripts upregulated in lesional skin (vs nonlesional and/or HV skin) suggested increased mast cell/leukocyte infiltration (FCER1G, C3AR1, CD93, S100A8, and S100A9), increased oxidative stress, vascularization (CYR61), and skin repair events (KRT6A, KRT16). Lesional signatures were not modulated by treatment in nonresponders (defined based on UAS7 longitudinal changes ≥16).
Omalizumab, in treatment responders, reverted transcriptional signatures associated with CSU lesion phenotype to reflect nonlesional/HV expression levels; this is consistent with observed omalizumab-mediated clinical improvement observed in patients with CSU.
奥马珠单抗是一种人源化重组单克隆抗 IgE 抗体，已被证明对慢性自发性荨麻疹（CSU）患者有效，包括重度和治疗抵抗性 CSU 患者。在此，我们报告奥马珠单抗对纳入双盲、安慰剂对照研究的 CSU 患者皮肤活检中基因表达的影响。
慢性自发性荨麻疹患者（18-75 岁）按 300mg 奥马珠单抗（n=20）或安慰剂（n=10）皮下注射，每 4 周 1 次，共 12 周（NCT01599637）。在同一患者同意的区域采集皮损和非皮损皮肤活检，并与 10 名未经治疗的健康志愿者（HV）的相同区域皮肤活检进行比较。使用 Affymetrix HG-U133Plus2.0 微阵列生成基因表达数据。使用 R 包进行统计分析。
基线时，皮损和非皮损皮肤之间有 63 个转录本存在差异表达。这些皮损特征中有三分之二在皮损和 HV 皮肤之间也存在差异表达。接受奥马珠单抗治疗后，超过 75%的皮损特征向非皮损皮肤表达水平转变（与安慰剂相比，P<0.01）。在皮损皮肤中上调的转录本提示肥大细胞/白细胞浸润增加（FCER1G、C3AR1、CD93、S100A8 和 S100A9）、氧化应激增加、血管生成（CYR61）和皮肤修复事件（KRT6A、KRT16）。在无应答者（根据 UAS7 纵向变化≥16 定义）中，皮损特征不受治疗调节。
在治疗应答者中，奥马珠单抗使与 CSU 皮损表型相关的转录特征恢复至反映非皮损/HV 表达水平；这与 CSU 患者中观察到的奥马珠单抗介导的临床改善一致。
