Understanding shared mechanisms of response to targeted therapies for eczema

特应性湿疹是一种常见的炎症性皮肤病，影响20%的儿童和10%的成年人1，2。它的特征是表皮屏障功能障碍和Th2炎症介质(IL-4/IL-13)的过度产生。最近的研究已经针对这些免疫分子提供了治疗方法，Dupiumab(一种生物阻断IL-4和IL-13的单抗)和Janus Kinase(JAK)抑制剂(下调多种细胞因子，包括IL-4和IL-13)显示出主要的益处3。然而，这些昂贵的药物(每名患者每年约10,000 GB)增加了本已相当可观的疾病经济负担。最近的一项网络荟萃分析进一步强调了药物反应和耐受性的个体间异质性4。患者经常循环使用多种药物来实现疾病控制，经历病情暴发、感染、不良反应。超过60%的人在服用杜匹单抗和JAK抑制剂7-10时无法获得透明/几乎透明的皮肤。眼睛副作用影响超过50%的Dupilumab和带状疱疹是JAK抑制剂11-13最常见的感染性并发症。这些问题反映了对这些药物如何作用的有限了解5，6。先前使用有限分辨率的微阵列和批量RNA-SEQ的研究表明，不同疗法的作用最终收敛于通过12-16周的治疗共同抑制中央致病Th2轴7，8。然而，缺乏头对头的比较器数据，并且缺乏对早期治疗效果的机制研究。这导致了对主要药物后果的认识不足，而不是抑制炎症级联反应的次要/下游影响。NIHR资助的Beacon多臂试验是解决这一重要研究差距的全球独一无二的机会。从2023年第二季度开始(共同领导Smith)，它将提供第一个关于主要类别湿疹疗法的临床有效性、耐受性和成本效益比较的正面证据。在这种背景下，单细胞(包括单核)方法有可能为治疗行动9-11提供高分辨率的机械性见解。这项技术的力量在癌症研究中得到了例证，它阐明了免疫治疗期间肿瘤免疫渗透的演变9。相反，在湿疹中，缺乏关于治疗效果的单细胞数据，也没有对新的靶向治疗进行比较分析13。问：湿疹靶向治疗的关键早期事件是什么？假设：不同的靶向治疗具有共同的早期作用机制，这些机制对其最终抑制湿疹Th2的效果至关重要。目的：在对这些药物表现出临床反应的BEAC参与者中，交叉靶向治疗Dupilumab(生物)和JAK抑制剂的早期作用。这将揭示驱动湿疹消退的早期共同变化。目标1：确定支持治疗行动的皮肤细胞亚群、细胞-细胞相互作用和基因调控网络的早期变化，并使用单核RNA-seq(SNRNA-seq)收敛于Th2轴抑制。目标2：定义支持皮肤治疗行动的细胞亚群和细胞-细胞相互作用的空间背景(如目标1所确定的)。目的3：通过免疫图谱分析来自信标队列的匹配血液样本来表征与血液中的药物作用和反应有关的细胞亚群。

Atopic eczema is a common inflammatory skin disease, affecting 20% of children and 10% of adults1,2. It is characterised by epidermal barrier dysfunction and excessive production of Th2 inflammatory mediators (IL-4/IL-13).Recent research has delivered therapies targeting these immune molecules, with dupilumab (a monoclonal antibody biologic blocking IL-4 and IL-13) and Janus kinase (JAK) inhibitors (downregulating multiple cytokines, including IL-4 and IL-13) showing major benefit3. However, these high-cost drugs (~£10,000 per patient per year) add to the already substantial economic burden of disease. A recent network meta-analysis further highlighted inter-individual heterogeneity in drug response and tolerability4. Patients often cycle through multiple drugs to achieve disease control, experiencing flares, infection, adverse effects. More than 60% fail to achieve clear/nearly clear skin on dupilumab and JAK inhibitors7-10. Eye side-effects impact more than 50% of those on dupilumab and herpes zoster is the commonest infectious complication of JAK inhibitors11-13.These problems reflect the limited understanding of how these drugs work5,6. Prior studies using the limited resolution of microarray and bulk RNA-seq suggest the action of different therapies ultimately converge on shared suppression of the central pathogenic Th2 axis by 12-16 weeks of treatment7,8. There is, however, a lack of head-to head comparator data and a paucity of mechanistic research into early treatment effects. This has led to a poor understanding of primary drug consequences as opposed to secondary/downstream effects of inhibiting inflammatory cascades. The NIHR-funded BEACON multi-arm trial is a globally unique opportunity to address this important research gap.Commencing Q2 2023 (co-lead Smith), it will provide the first head-to-head evidence on comparative clinical effectiveness, tolerability and cost effectiveness of the major classes of eczema therapies. In this context, single cell (including single nuclear) methods have the potential to provide high resolution mechanistic insights into treatmentactions 9-11. The power of this technology is exemplified in cancer research, where it has illuminated the evolution of tumour immune infiltrates during immunotherapy9,12. Conversely, in eczema there is a paucity of single cell data on treatment effects and no comparative analyses of novel targeted therapies13. Question: What are the critical early events that mediate shared response to targeted therapies in eczema?Hypothesis: Different targeted therapies share early mechanisms of action that are critical to their ultimate effects on Th2 suppression in eczema.Objective: To intersect the early actions of the targeted therapies dupilumab (biologic) and JAK inhibitors in BEACONparticipants who show a clinical response to these drugs. This will uncover early shared changes that drive eczema resolution.Aim 1: Identify early changes in skin cell subpopulations, cell-cell interactions and gene regulatory networks that underpin treatment actions and converge upon Th2 axis suppression using single nuclear RNA-seq (snRNA-seq).Aim 2: Define the spatial context of the cell subpopulations and cell-cell interactions underpinning treatment actionsin skin (as identified in Aim 1). Aim 3: Characterise the cell subpopulations implicated in drug action and response in blood by immune profiling matched blood samples from the BEACON cohort.