Omalizumab normalizes the gene expression signature of lesional skin in patients with chronic spontaneous urticaria: a randomized, double-blind, placebo-controlled study

Introduction and objectives. Chronic spontaneous urticaria (CSU), including severe and treatment-refractory CSU, shows a strong response to omalizumab, a humanized recombinant monoclonal anti-IgE antibody. The effect of omalizumab on gene expression was assessed in skin biopsies from CSU patients enrolled in a double-blind placebo-controlled study (ClinicalTrials.gov Identifier: NCT01599637). Methods. CSU 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. Lesional and non-lesional skin biopsies were collected from the same body area of consenting subjects and assessed at baseline and on Day 85. Skin biopsies from the same area of 10 untreated healthy volunteers (HV) were also processed as reference. Gene expression data were generated using Affymetrix HG-U133plus2.0 microarrays. Statistical analyses were performed using R packages. In brief, after normalization, low-intensity transcripts (i.e. probesets with intensities less than 100 in ≥50% of the samples) were filtered out. To identify transcriptional changes, linear models were constructed taking into account the type of biopsy (lesional or non-lesional), the study visit and the treatment for each patient. Thresholds for statistical significance and minimal fold change (FC) were defined as P-value ≤0.05 (no multiple testing correction) and absolute FC ≥1.5, respectively. Results. At baseline, 63 transcripts were differentially expressed between lesional and non-lesional skin. Two thirds of this lesional signature was also differentially expressed between lesional and HV skin. Upon treatment with omalizumab, over 75% of this lesional signature changed to reflect non-lesional skin expression levels (different to placebo, P-value 16). Conclusions. Omalizumab, in treatment responders, reverted transcriptional signatures associated with the CSU lesion phenotype to reflect non-lesional/HV expression levels. This result is consistent with observed omalizumab-mediated clinical improvement observed in patients with CSU