Transcriptomic profiling of plaque psoriasis and cutaneous T cell subsets during treatment with secukinumab
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ABSTRACT:
PROVIDER: PRJNA718090 | ENA |
REPOSITORIES: ENA
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Project description:The IL-17A inhibitor secukinumab is efficacious for the treatment of psoriasis. To better understand its mechanism of action, we investigated its impact on psoriatic lesions from 15 moderate-to-severe plaque psoriasis patients undergoing secukinumab treatment. We characterized the longitudinal transcriptomic changes of whole lesional skin tissue as well as cutaneous CD4+ and CD8+ T effector cells and CD4+ T regulatory cells across 12 weeks of treatment. Secukinumab was clinically effective and reduced disease-associated overexpression of IL17A, IL17F, IL23A, IL23R, and IFNG in whole tissue as soon as 2 weeks after initiation of treatment. IL17A overexpression in T cell subsets, primarily CD8+ T cells, was also reduced. While secukinumab treatment resolved 89-97% of psoriasis-associated expression differences in bulk tissue and T cell subsets by week 12 of treatment, we observed expression differences involved in interferon signaling and metallothionein synthesis that remained unresolved at this time point as well as potential treatment-associated expression differences involved in IL-15 signaling. These changes were accompanied by shifts in broader immune cell composition based on deconvolution of RNA-seq data. In conclusion, our study reveals several phenotypic and cellular changes within the lesion that underlie clinical improvement from secukinumab.
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Project description:Exploratory study on the kinetics of psoriasis symptoms, pruritus intensity and lesional biomarkers in patients with moderate to severe plaque-type psoriasis treated with subcutaneous secukinumab (300 mg) during a 16 week open-label run-in phase followed by a 16 week randomized, double-blind, placebo-controlled withdrawal phase.
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Project description:The role of gut microbiome dysbiosis in the pathogenesis of psoriasis has gained increasing attention in recent years. Secukinumab, targeting interleukin (IL)-17, has a promising efficacy in psoriasis treatment. However, it remains unclear the gut microbiota alteration and related functional changes caused by successful secukinumab therapy in psoriatic patients. In our study, we compared fecal microbiome profile between psoriatic patients after secukinumab successful treatment (AT) and the other two groups, psoriatic patients without therapy (BT) and healthy people (H), respectively by using next-generation sequencing targeting 16S ribosomal RNA. Then, shotgun metagenomic sequencing was firstly used to characterize bacterial gut microbial communities and related functional change in AT group. We found that the diversity and structure of the microbial community in AT group were significantly changed compared to that of BT group and H group. AT group showed a microbiota profile characterized by increased proportions of the phylum Firmicute, families Ruminococcaceae, and a reduction in the phylum Bacteroidota (elevated F/B ratio). To detect functional alteration, we discovered that secukinumab treatment may construct a more stable homeostasis of gut microbiome with functional alteration. There were different KEGG pathways such as downregulated cardiovascular diseases pathway and upregulated infectious diseases in AT group. By metagenomic analysis, metabolic functional pathway was changed after secukinumab therapy. It seems that gut microbiota investigation during biologic drug treatment is useful for predicting the efficacy and risks of drug treatment in disease.
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Project description:The role of gut microbiome dysbiosis in the pathogenesis of psoriasis has gained increasing attention in recent years. Secukinumab, targeting interleukin (IL)-17, has a promising efficacy in psoriasis treatment. However, it remains unclear the gut microbiota alteration and related functional changes caused by successful secukinumab therapy in psoriatic patients. In our study, we compared fecal microbiome profile between psoriatic patients after secukinumab successful treatment (AT) and the other two groups, psoriatic patients without therapy (BT) and healthy people (H), respectively by using next-generation sequencing targeting 16S ribosomal RNA. Then, shotgun metagenomic sequencing was firstly used to characterize bacterial gut microbial communities and related functional change in AT group. We found that the diversity and structure of the microbial community in AT group were significantly changed compared to that of BT group and H group. AT group showed a microbiota profile characterized by increased proportions of the phylum Firmicute, families Ruminococcaceae, and a reduction in the phylum Bacteroidota (elevated F/B ratio). To detect functional alteration, we discovered that secukinumab treatment may construct a more stable homeostasis of gut microbiome with functional alteration. There were different KEGG pathways such as downregulated cardiovascular diseases pathway and upregulated infectious diseases in AT group. By metagenomic analysis, metabolic functional pathway was changed after secukinumab therapy. It seems that gut microbiota investigation during biologic drug treatment is useful for predicting the efficacy and risks of drug treatment in disease.
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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.
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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 by microarray analysis to explore the molecular transformation in skin samples from psoriatic patients during anti-IL-17A (secukinumab) treatment.
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