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Neutrophil and whole blood RNAseq from Generalised Pustular Psoriasis patients and healthy individuals

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE123787 | GEO | 2019/01/18

REPOSITORIES: GEO

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Whole blood RNAseq from Generalised Pustular Psoriasis patients and healthy individuals

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Pharmacokinetics of Risankizumab in Asian Healthy Subjects and Patients With Moderate to Severe Plaque Psoriasis, Generalized Pustular Psoriasis, and Erythrodermic Psoriasis.

Project description:Risankizumab, a humanized monoclonal antibody that targets interleukin-23 p19 subunit, was developed for the treatment of psoriasis. This work characterizes risankizumab pharmacokinetics in Japanese and Chinese healthy subjects compared with white healthy subjects and in Japanese patients with moderate to severe plaque psoriasis, generalized pustular psoriasis, or erythrodermic psoriasis. A phase 1, single-dose study evaluated risankizumab pharmacokinetics and safety/tolerability in healthy white (18 and 300 mg subcutaneous [SC]), Japanese (18, 90, and 300 mg SC and 200, 600, and 1200 mg intravenous [IV]), and Chinese (18, 90, and 300 mg SC) subjects; pharmacokinetic data were analyzed using noncompartmental methods. Risankizumab pharmacokinetic data from phase 2/3 studies in Japanese patients with plaque psoriasis, generalized pustular psoriasis, or erythrodermic psoriasis following multiple SC doses of 75 mg or 150 mg were analyzed using a population pharmacokinetic approach along with data from the phase 1 and global phase 1 to 3 studies. Risankizumab plasma exposures (peak plasma concentration and area under the concentration-time curve) were approximately dose-proportional across 18- to 300-mg SC or 200- to 1200-mg IV doses. Risankizumab terminal elimination half-life (harmonic mean 27-34 days) was comparable across doses and ethnicities. Risankizumab exposures were approximately 20% to 30% higher in Japanese and Chinese healthy subjects compared with white healthy subjects or in Japanese patients compared with non-Japanese patients. After accounting for body-weight differences, risankizumab exposures were comparable across ethnicities. Overall, there was no ethnic impact on risankizumab pharmacokinetics, and the small difference in exposure due to body weight has no clinical relevance.

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Comparison of healthy, plaque psoriasis and pustular psoriasis FFPE skin biopsies

Project description:Generalized pustular psoriasis (GPP) is a rare, debilitating, and often life-threatening inflammatory disease characterized by episodic infiltration of neutrophils into the skin, pustule development, and systemic inflammation, which can manifest in the presence or absence of chronic plaque psoriasis (PV). Current treatments are unsatisfactory thus a better understanding the pathogenesis of GPP is warranted. To assess the pathophysiological differences between GPP and PV we performed a gene expression study on formalin-fixed paraffin-embedded biopsies of GPP (n=30) and PV (n=12) lesions and healthy control (n=20) skin. Compared with healthy skin, GPP lesions yielded 365 and PV 898 differentially expressed genes respectively, with 190 upregulated in both diseases. We detected higher expression of IL-1 and IL-36 cytokines in GPP lesions compared with PV, and this occurred proximal to neutrophils. We show both activated neutrophils and isolated neutrophil proteases can activate IL-36. Diverging from the Th1/Th17 pathophysiology of PV, significantly fewer IL23A, IL17A, IFNG, CXCL9, CXCL10 and MX1 transcripts were detected in GPP lesions. Our data indicate a level of sustained activation of IL-1 and IL-36 in GPP, inducing neutrophil chemokine expression, infiltration and pustule formation, suggesting that the IL-1 and IL-36 inflammatory axes are the main drivers of disease pathology in GPP.

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