British Association of dermatologists guidelines for biologic therapy for psoriasis 2020 – a rapid update

The overall aim of the guideline is to provide up‐to‐date, evidence‐based recommendations on the use of biologic therapies targeting TNF (adalimumab, etanercept, certolizumab pegol, infliximab), IL12/23p40 (ustekinumab), IL17A (ixekizumab, secukinumab), IL17RA (brodalumab) and IL23p19 (guselkumab, risankizumab, tildrakizumab) in adults, children and young people for the treatment of psoriasis; consideration is given to the specific needs of people with psoriasis and psoriatic arthritis

A Framework for Multi-Omic Prediction of Treatment Response to Biologic Therapy for Psoriasis.

Biologic therapies have shown high efficacy in psoriasis, but individual response varies and is poorly understood. To inform biomarker discovery in the Psoriasis Stratification to Optimise Relevant Therapy (i.e., PSORT) study, we evaluated a comprehensive array of omics platforms across three time points and multiple tissues in a pilot investigation of 10 patients with severe psoriasis, treated with the tumor necrosis factor (TNF) inhibitor, etanercept. We used RNA sequencing to analyze mRNA and small RNA transcriptome in blood, lesional and nonlesional skin, and the SOMAscan platform to investigate the serum proteome. Using an integrative systems biology approach, we identified signals of treatment response in genes and pathways associated with TNF signaling, psoriasis pathology, and the major histocompatibility complex region. We found association between clinical response and TNF-regulated genes in blood and skin. Using a combination of differential expression testing, upstream regulator analysis, clustering techniques, and predictive modeling, we show that baseline samples are indicative of patient response to biologic therapies, including signals in blood, which have traditionally been considered unreliable for inference in dermatology. In conclusion, our pilot study provides both an analytical framework and empirical basis to estimate power for larger studies, specifically the ongoing PSORT study, which we show as powered for biomarker discovery and patient stratification

Anakinra for palmoplantar pustulosis: results from a randomized, double-blind, multicentre, two staged, adaptive placebo controlled trial (APRICOT)

Background Palmoplantar pustulosis (PPP) is a rare, debilitating, chronic inflammatory skin disease affecting the hands and feet. Clinical, immunological and genetic findings suggest a pathogenic role for interleukin (IL)-1. Objective To determine whether anakinra (an IL-1 receptor antagonist) delivers therapeutic benefit for PPP. Methods A randomised (1:1), double-blind, two-staged, adaptive, UK multi-centre, placebo-controlled trial. Participants had a diagnosis of PPP (>6 months) requiring systemic therapy. Treatment was eight weeks of anakinra or placebo via daily self-administered subcutaneous injections. The primary outcome was the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at 8 weeks. Results A total of 374 patients were screened and 64 were enrolled (31 anakinra, 33 placebo) with mean baseline PPPASI 17.8 (SD=10.5); PPP investigator’s global assessment severe (50%) or moderate (50%). The baseline adjusted mean difference in PPPASI favoured anakinra but did not demonstrate superiority in intention-to-treat analysis, -1.65, 95% CI [-4.77 to 1.47], p=0.300. Secondary objective measures including fresh pustule count (2.94, 95% CI [-26.44 to 32.33] favouring anakinra), total pustule count (-30.08, 95% CI [-83.20 to 23.05] favouring placebo), and patient-reported outcomes, similarly did not show superiority of anakinra. When modelling the impact of adherence, the PPPASI complier average causal effect (CACE) for an individual who receives ≥90% total treatment (48% anakinra group), was -3.80, 95% CI [-10.76 to 3.16], p=0.285. No serious adverse events occurred. Conclusions No evidence for superiority of anakinra was found. IL-1 blockade is not a useful intervention for the treatment of PPP

Single-cell analysis implicates Th17-to-Th2 cell plasticity in the pathogenesis of palmoplantar pustulosis

Background Palmoplantar 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. Objective We sought to investigate the immune pathways that underlie the pathogenesis of PPP. Methods We 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 Results Bulk 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. Conclusions These 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. Clinical implications The simultaneous activation of Th17 and Th2 responses in PPP supports the therapeutic use of agents that inhibit multiple T-cell pathways

Dynamic Performance of Unimorph Piezoelectric Bending Actuators

Piezoelectric bending actuators utilise the inverse piezoelectric effect to convert input electric energy to useful mechanical work. A comprehensive analytical model of the dynamic electromechanical behaviour of a unimorph piezoelectric actuator has been developed and successfully validated against experimental data. The model provides a mapping between force, displacement, voltage and charge. Damping is modelled using experimental data. Experimental validation is based on measurement of mode shape and frequency response of a series of unimorph beams of varying length but of the same thickness and material. The experimental frequency response is weakly nonlinear with excitation voltage, with a reduction in natural frequency and increase in damping with increasing excitation amplitude. An expression for the electromechanical coupling factor has been extracted from the analytical model and is used as the objective for parametric design studies. The design parameters are thickness and Young’s modulus ratios of the elastic and piezoceramic layers, and the piezoelectric constant k31. The operational design point is defined by the damping ratio. It is found that the relative variation in the electromechanical coupling factor with the design parameters for dynamic operation is similar to static operation; however, for light damping, the magnitude of the peak electromechanical coupling factor will typically be an order of magnitude greater than that of static operation. For the actuator configuration considered in this study, it is shown that the absolute variation in electromechanical coupling factor with thickness ratio for dynamic operation is same as that for static operation when the damping ratio is 0.44. </jats:p

UVR-induced oxidative stress in human skin in vivo: effects of oral vitamin C supplementation

Previous studies of cultured skin cells and murine skin in vivo have indicated that UVR-induced damage involves the generation of reactive oxygen species and depletion of endogenous antioxidant systems. In order to explore the relevance of this to UVR-induced damage to human skin, we have undertaken a detailed examination of the time-course of changes in markers of oxidative stress in human skin following exposure to physiological amounts of UVR in vivo. In addition, we have examined the skin bioavailability of a common nutritional antioxidant, vitamin C, and have assessed the effects of supplementation on markers of oxidative stress. Our hypothesis was that acute exposure of human skin to UVR in vivo would lead to oxidation of cellular biomolecules that could be prevented by prior vitamin C treatment. A UVR-challenge of 120 mJ/cm2 of broadband UVB (peak 310 nm, range 270–400 nm) was applied to buttock skin of 8 healthy volunteers. This caused a rapid and significant rise in activity of skin catalase at 1 h and an increase in the oxidized/total glutathione ratio at 6 h post-UVR. AP-1 DNA binding also peaked at 1–6 h post-UVR, then declined rapidly to baseline levels. No significant changes were seen in skin malonaldehyde content. Oral vitamin C supplements (500 mg/day) were taken by 12 volunteers for 8 weeks resulting in significant rises in plasma and skin vitamin C content. Supplementation had no effect on the UVR-induced erythemal response. The skin malonaldehyde content was reduced by vitamin C supplementation, but surprisingly, reductions in the skin content of total glutathione and protein thiols were also seen. We speculate that this apparently paradoxical effect could be due to regulation of total reductant capacity by skin cells, such that vitamin C may have been replacing other reductants in these cells. No evidence was obtained for an effect of the supplementary vitamin C on the mild oxidative stress seen in human skin following UVR exposure