Understanding shared mechanisms of response to targeted therapies for eczema

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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.