Project description:Biologics targeting the tumour necrosis factor (TNF) and interleukin (IL)-17/23 axis are highly effective treatments for psoriasis but can result in cutaneous adverse events. The pathogenesis of paradoxical eczema, the occurrence of an atopic dermatitis phenotype after biologic initiation in people with psoriasis, is unknown. Using single cell RNA-seq and mass cytometry, we found increased expression of TNF, interferon (IFN)-γ and IFN-α and their signalling pathways in paradoxical eczema case cell clusters compared with matched psoriasis controls. Genetic variants influencing expression of TNF pathway genes were associated with paradoxical eczema in a separate genotyped cohort, and this association was independent of known atopic risk loci. This suggests that paradoxical eczema has a predominantly type 1 systemic inflammatory signature, and that genetic susceptibility to aberrant TNF pathway signalling could contribute to development of this phenotype during biologic treatment.
Project description:Comparing molecular signatures of psoriasis and eczema in patients co-affected by both diseases provides a comprehensive understanding of disease pathogenesis as well as a diagnostic tool to differentiate these widespread inflammatory skin diseases. In patients affected by both psoriasis and non-atopic or atopic eczema simultaneously (n=24), whole genome expression arrays of psoriasis, eczema, and non-involved skin were performed Arrays MQ_35 and MQ_41 did not pass quality control and thus were not normalized and were excluded from this Series.
Project description:ImportanceBiologics used for plaque psoriasis have been reported to be associated with an atopic dermatitis (AD) phenotype, or paradoxical eczema, in some patients. The risk factors for this are unknown.ObjectiveTo explore risk of paradoxical eczema by biologic class and identify factors associated with paradoxical eczema.Design, setting, and participantsThis prospective cohort study used data from the British Association of Dermatologists Biologics and Immunomodulators Register for adults treated with biologics for plaque psoriasis who were seen at multicenter dermatology clinics in the UK and Ireland. Included participants were registered and had 1 or more follow-up visits between September 2007 and December 2022.ExposuresDuration of exposure to tumor necrosis factor (TNF) inhibitors, interleukin (IL) 17 inhibitors, IL-12/23 inhibitors, or IL-23 inhibitors until paradoxical eczema onset, treatment discontinuation, last follow-up, or death.Main outcomes and measuresIncidence rates of paradoxical eczema, paradoxical eczema risk by biologic class, and the association of demographic and clinical variables with risk of paradoxical eczema were assessed using propensity score-weighted Cox proportional hazards regression models.ResultsOf 56 553 drug exposures considered, 24 997 from 13 699 participants were included. The 24 997 included exposures (median age, 46 years [IQR, 36-55 years]; 57% male) accrued a total exposure time of 81 441 patient-years. A total of 273 exposures (1%) were associated with paradoxical eczema. The adjusted incidence rates were 1.22 per 100 000 person-years for IL-17 inhibitors, 0.94 per 100 000 person-years for TNF inhibitors, 0.80 per 100 000 person-years for IL-12/23 inhibitors, and 0.56 per 100 000 person-years for IL-23 inhibitors. Compared with TNF inhibitors, IL-23 inhibitors were associated with a lower risk of paradoxical eczema (hazard ratio [HR], 0.39; 95% CI, 0.19-0.81), and there was no association of IL-17 inhibitors (HR, 1.03; 95% CI, 0.74-1.42) or IL-12/23 inhibitors (HR, 0.87; 95% CI, 0.66-1.16) with risk of paradoxical eczema. Increasing age (HR, 1.02 per year; 95% CI, 1.01-1.03) and history of AD (HR, 12.40; 95% CI, 6.97-22.06) or hay fever (HR, 3.78; 95% CI, 1.49-9.53) were associated with higher risk of paradoxical eczema. There was a lower risk in males (HR, 0.60; 95% CI, 0.45-0.78).Conclusions and relevanceIn this study, in biologic-treated patients with psoriasis, paradoxical eczema risk was lowest in patients receiving IL-23 inhibitors. Increasing age, female sex, and history of AD or hay fever were associated with higher risk of paradoxical eczema. The overall incidence of paradoxical eczema was low. Further study is needed to replicate these findings.
Project description:Psoriasis is a common chronic inflammatory skin disease where IκBζ is known to play an important role by mediating IL-17A-driven effects. However, the molecular mechanism by which IL-17A regulates IκBζ expression is not known. We assessed global gene expression my microarray analysis to explore the molecular transformation in blood samples from psoriatic patients during anti-IL-17A (secukinumab) treatment.
Project description:Psoriasis is a worldwide chronic inflammatory skin disease. The treatment is usually designed according to its severity. In this research, RNA-seq was performed on the peripheral blood mononuclear cells (PBMCs) of 12 patients with psoriasis before and after treatment (4 week) of guselkumab.
Project description:Comparing molecular signatures of psoriasis and eczema in patients co-affected by both diseases provides a comprehensive understanding of disease pathogenesis as well as a diagnostic tool to differentiate these widespread inflammatory skin diseases.
Project description:Dupilumab is an antibody targeting the IL-4/IL-13 receptors indicated for atopic dermatitis patients, but paradoxical psoriasis-like reactions have been reported under treatment. To understand the pathogenesis of DI-Pso, we performed a gene expression profiling study using microarray on skin biopsies of dupilumab-induced psoriasis, plaque psoriasis and AD compared with healthy control skin.
Project description:Development of a real-time PCR based molecular classifier to distinguish psoriasis from eczema in FFPE-fixed skin samples and evaluation of the use of minimally invasive microbiopsies and tape strips for molecular diagnosis.