National Heart and Lung Institute, the Imperial College London, London, United Kingdom; NIHR Imperial Biomedical Research Centre, London, United Kingdom; Data Science Institute, Imperial College London, London, United Kingdom.
Laboratory of Inflammatory Skin Diseases, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Biomedical Engineering, The University of Mississippi, Oxford, Miss.
J Allergy Clin Immunol. 2022 Jan;149(1):89-101. doi: 10.1016/j.jaci.2021.04.010. Epub 2021 Apr 20.
Transcriptomic changes in patients who respond clinically to biological therapies may identify responses in other tissues or diseases.
We sought to determine whether a disease signature identified in atopic dermatitis (AD) is seen in adults with severe asthma and whether a transcriptomic signature for patients with AD who respond clinically to anti-IL-22 (fezakinumab [FZ]) is enriched in severe asthma.
An AD disease signature was obtained from analysis of differentially expressed genes between AD lesional and nonlesional skin biopsies. Differentially expressed genes from lesional skin from therapeutic superresponders before and after 12 weeks of FZ treatment defined the FZ-response signature. Gene set variation analysis was used to produce enrichment scores of AD and FZ-response signatures in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes asthma cohort.
The AD disease signature (112 upregulated genes) encompassing inflammatory, T-cell, T2, and T17/T22 pathways was enriched in the blood and sputum of patients with asthma with increasing severity. Patients with asthma with sputum neutrophilia and mixed granulocyte phenotypes were the most enriched (P < .05). The FZ-response signature (296 downregulated genes) was enriched in asthmatic blood (P < .05) and particularly in neutrophilic and mixed granulocytic sputum (P < .05). These data were confirmed in sputum of the Airway Disease Endotyping for Personalized Therapeutics cohort. IL-22 mRNA across tissues did not correlate with FZ-response enrichment scores, but this response signature correlated with T22/IL-22 pathways.
The FZ-response signature in AD identifies severe neutrophilic asthmatic patients as potential responders to FZ therapy. This approach will help identify patients for future asthma clinical trials of drugs used successfully in other chronic diseases.
对生物治疗有临床反应的患者的转录组变化可能会在其他组织或疾病中识别出反应。
我们试图确定在患有严重哮喘的成年人中是否存在特应性皮炎（AD）中鉴定出的疾病特征，以及对接受抗 IL-22（fezakinumab [FZ]）治疗的 AD 患者具有临床反应的转录组特征是否在严重哮喘中丰富。
从 AD 病变和非病变皮肤活检的差异表达基因分析中获得 AD 疾病特征。在 12 周的 FZ 治疗前后，治疗超级应答者的病变皮肤中的差异表达基因定义了 FZ 反应特征。使用基因集变异分析（gene set variation analysis）在 Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes 哮喘队列中产生 AD 和 FZ 反应特征的富集分数。
AD 疾病特征（112 个上调基因）包括炎症、T 细胞、T2 和 T17/T22 途径，在哮喘严重程度增加的患者的血液和痰液中富集。痰液嗜中性粒细胞和混合粒细胞表型的哮喘患者最丰富（P<.05）。FZ 反应特征（296 个下调基因）在哮喘患者的血液中富集（P<.05），特别是在嗜中性粒细胞和混合粒细胞痰液中（P<.05）。这些数据在气道疾病个体化治疗的表型分类队列的痰液中得到了证实。组织中的 IL-22 mRNA 与 FZ 反应富集分数不相关，但这种反应特征与 T22/IL-22 途径相关。
AD 中的 FZ 反应特征鉴定出严重嗜中性粒细胞性哮喘患者可能对 FZ 治疗有反应。这种方法将有助于为未来在其他慢性疾病中成功使用的药物治疗哮喘的临床试验确定患者。
