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Background\ud\udPalmoplantar pustulosis (PPP) is a severe inflammatory skin disorder, characterised by eruptions of painful, neutrophil-filled pustules on the palms and soles. While PPP has a profound effect on quality of life, it remains poorly understood and notoriously difficult to treat.\udObjective\ud\udWe sought to investigate the immune pathways that underlie the pathogenesis of PPP.\udMethods\ud\udWe applied bulk- and single-cell RNA-sequencing methods to the analysis of skin biopsies and peripheral blood mononuclear cells. We validated our results by flow cytometry and immune fluorescence microscopy\udResults\ud\udBulk RNA-sequencing of patient skin detected an unexpected signature of T-cell activation, with a significant overexpression of several Th2 genes typically upregulated in atopic dermatitis. To further explore these findings, we carried out single-cell RNA-sequencing in peripheral blood mononuclear cells of healthy and affected individuals. We found that the memory CD4+T-cells of PPP patients were skewed towards a Th17 phenotype, a phenomenon that was particularly significant among CLA+ skin-homing cells. We also identified a subset of memory CD4+ T-cells which expressed both Th17 (KLRB1/CD161) and Th2 (GATA3) markers, with pseudo-time analysis suggesting that the population was the result of Th17 to Th2 plasticity. Interestingly, the GATA3+/CD161+ cells were over-represented among the PBMCs of affected individuals, both in the scRNA-seq dataset and in independent flow-cytometry experiments. Dual positive cells were also detected in patient skin by means of immune fluorescence microscopy.\udConclusions\ud\udThese observations demonstrate that PPP is associated with complex T-cell activation patterns and may explain why biologics that target individual T-helper populations have shown limited therapeutic efficacy.\udClinical implications\ud\udThe simultaneous activation of Th17 and Th2 responses in PPP supports the therapeutic use of agents that inhibit multiple T-cell pathways.

Treatment with baricitinib in combination with topical corticosteroids previously showed greater improvements in itch and sleep versus placebo in adults with moderate-to-severe AD.To assess whether improvements in itch and sleep translate to greater quality of life (QoL), productivity and treatment benefit in AD.In this post hoc analysis with data from BREEZE-AD7 (NCT03733301), itch and sleep improvements at Week 16 were defined by ≥4-point improvements in the Itch Numeric Rating Scale and ≥1.5 decreases in the number of night-time awakenings since baseline, respectively. Dermatology Life Quality Index, Work Productivity and Activity Impairment-AD and Patient Benefit Index (PBI) scores were compared in patients with and without improvements. Proportions were analysed using logistic regression with non-responder imputation. Changes from baseline were calculated using ANCOVA, with last observation carried forward. Least square mean PBI scores were assessed using ANOVA.More patients with itch improvement versus no itch improvement reported no impact of AD on QoL (28.4% vs. 6.0%). Daily activity impairment was lower in patients with itch improvement (-39.6% vs. -15.6%). A greater proportion of patients with sleep improvement versus no sleep improvement had no AD-related impact on QoL (24.1% vs. 1.5%). Patients with sleep improvement had less daily activity impairment (-35.0% vs. -18.5%). Patients with itch and sleep improvements experienced greater treatment benefit.Patients with AD who experienced clinically meaningful improvements in itch and sleep following treatment had significantly better QoL, productivity and treatment benefit. Addressing these symptoms is important to achieving meaningful and patient-relevant improvements in well-being.