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Blood Transcriptome Signature as Indicator and Predictor for Efficacy of Abrocitinib in Treatment of Atopic
Yu Wang1, Huibin Yin1, Zheng Li1
1Department of Dermatology, Shanghai Institute of Dermatology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
Abstract:
Patients with atopic dermatitis (AD) exhibit significant blood transcriptome alterations, reflecting systemic inflammation. The effects of abrocitinib, a Jak1 inhibitor, on the blood transcriptome of AD remain unclear. This study aimed to investigate abrocitinib's effects on the blood transcriptome in patients with AD and identify transcriptomic predictors of treatment efficacy. Blood cell mRNA sequencing was conducted on 31 patients with AD at baseline and 4 and 12 weeks of 100 mg abrocitinib daily treatment. Differential gene expression, immune infiltration, and weighted gene coexpression network analyses were performed, along with correlation analysis of transcriptomic data and clinical traits. We observed that abrocitinib treatment significantly improved clinical signs of AD. Correspondingly, blood transcriptome normalization, including downregulation of T helper 2, T helper 1, and eosinophil and an increase in type 1 regulatory T-cell abundance, rapidly occurred by week 4, with slight rebound by week 12. Higher baseline eosinophil counts predicted greater transcript normalization. Weighted gene coexpression network analyses identified an efficacy-related gene module, leading to a 5-gene (PLIN2, CAT, CLC, RAB44, and SMPD3) efficacy-predictive model, which was validated in another independent cohort of 30 patients with AD treated with abrocitinib. In conclusion, abrocitinib treatment resulted in rapid and extensive normalization of the dysregulated blood transcripts in AD, which was associated with its clinical efficacy.
Insights
Abrocitinib rapidly normalizes blood gene expression in atopic dermatitis (AD) patients, improving clinical symptoms. Higher baseline eosinophil counts predict better transcriptomic response to this JAK1 inhibitor treatment.
Area of Science:
- Immunology
- Genomics
- Dermatology
Background:
- Atopic dermatitis (AD) is characterized by systemic inflammation with significant blood transcriptome alterations.
- The impact of JAK1 inhibitors, such as abrocitinib, on the AD blood transcriptome is not well understood.
Purpose of the Study:
- To investigate the effects of abrocitinib on the blood transcriptome in AD patients.
- To identify transcriptomic predictors of abrocitinib treatment efficacy.
Main Methods:
- Blood mRNA sequencing was performed on 31 AD patients at baseline and weeks 4 and 12 during daily 100 mg abrocitinib treatment.
- Analyses included differential gene expression, immune cell infiltration, weighted gene coexpression networks, and correlation with clinical traits.
- A 5-gene predictive model for treatment efficacy was developed and validated in an independent cohort.
Main Results:
- Abrocitinib treatment significantly improved clinical AD symptoms.
- Rapid blood transcriptome normalization, including immune cell profile changes, occurred by week 4.
- Higher baseline eosinophil counts correlated with greater transcript normalization, and a 5-gene model predicted efficacy.
Conclusions:
- Abrocitinib treatment leads to rapid and broad normalization of the dysregulated blood transcriptome in AD patients.
- This transcriptomic normalization is associated with the drug's clinical efficacy.
- Baseline eosinophil levels and a novel 5-gene signature may predict treatment response.
