Blood expression data from psoriasis patients treated with secukinumab
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE137220 | GEO | 2021/03/26
REPOSITORIES: GEO
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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.
2021-03-26 | GSE137218 | GEO
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.
2021-09-06 | GSE171012 | GEO
Project description:To investigate treatment effects of secukinumab on clinical signs and psoriatic inflammation markers over 52 weeks in patients with psoriasis.
2023-03-24 | GSE201827 | GEO
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.
2023-08-07 | GSE239720 | GEO
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.
2023-08-07 | GSE239719 | GEO
Project description:Background: The pathogenesis of pityriasis rubra pilaris (PRP) is not completely understood, but interleukin (IL)-17 has been shown to play a critical role. There are no reliable immunomodulatory agents to treat PRP. We conducted an open-label, single-arm clinical trial of secukinumab, a monoclonal antibody that inhibits IL-17A, for the treatment of PRP. Objectives: To evaluate the clinical efficacy of secukinumab and define the transcriptomic landscape of PRP and its response to IL-17A blockade. Methods: Twelve patients with PRP were recruited for an open-label trial of secukinumab. Patients received a 24-week course of secukinumab. The primary endpoint was a ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75) from baseline to week 28. Secondary endpoints included PASI 90, change in Physician's Global Assessment (PGA), and change in Dermatology Life Quality Index (DLQI). RNA sequencing was performed on lesional and nonlesional skin biopsies obtained at baseline and week 2. Sample groups were compared to identify differential gene expression and pathway enrichment. This trial was registered with ClinicalTrials.gov: 'Cosentyx (secukinumab) for the treatment of adult onset pityriasis rubra pilaris' - NCT03342573. Results: At week 28, six of 11 patients (55%) achieved PASI 75, and three patients (27%) achieved PASI 90. PGA (P = 0.008) and DLQI scores (P = 0.010) showed significant improvement with treatment. No serious treatment-related adverse events were encountered. Treatment with secukinumab normalized transcriptional differences between lesional and nonlesional skin. Transcriptomic data from nonresponsive patients suggest that overactivity of innate immune pathways may be driving resistance to secukinumab. Conclusions: Secukinumab appears to be an effective treatment for PRP and warrants further investigation. PRP is a transcriptionally heterogeneous disease, reflecting its variable response to therapy. Agents targeting other IL-17 isoforms and innate immune mediators should be considered for future clinical trials. What is already known about this topic? The pathogenesis of pityriasis rubra pilaris is incompletely understood. Successful treatment has been reported with a variety of immunomodulatory agents, but disease is often refractory to therapy. Interleukin (IL)-17 is thought to drive keratinocyte proliferation and vascular dysfunction in this disease. A previous trial demonstrated efficacy of the anti-IL-17A drug ixekizumab for pityriasis rubra pilaris. What does this study add? Herein we describe the findings of a clinical trial of secukinumab, an anti-IL-17A monoclonal antibody, for the treatment of pityriasis rubra pilaris. Secukinumab was effective in treating pityriasis rubra pilaris. Our transcriptomic data give new insight into the expressional changes that occur in response to secukinumab and suggest mechanisms of treatment resistance.
2024-04-23 | GSE262954 | GEO
Project description:Interleukin-17A (IL-17A) is a key mediator of protective immunity to yeast and bacterial infections but also drives the pathogenesis of several autoimmune diseases, such as psoriasis or psoriatic arthritis. Here, we show that the tetra-transmembrane protein CMTM4 is a subunit of the IL-17 receptor (IL-17R). CMTM4 constitutively associated with IL-17R subunit C (IL-17RC) to mediate its stability, posttranslational modification, and plasma membrane localization. Both mouse and human cell lines deficient in CMTM4 were largely unresponsive to IL-17A, due to their inability to assemble the IL-17 receptor signaling complex. Accordingly, CMTM4-deficient mice were largely resistant to experimental psoriasis. Collectively, our data identified CMTM4 as an essential component of the IL-17 receptor and a potential therapeutic target for treating IL-17-mediated autoimmune diseases.
2022-12-02 | PXD036366 | Pride
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.
2018-12-31 | GSE102725 | GEO
Project description:Adalimumab and secukinumab are commonly used for moderate-severe psoriasis vulgaris (PV), but distinct individual response and impaired effectiveness happen occasionally. Little is known about it. Here, we report a proteomic analysis of psoriatic lesions from patients treated with these drugs using Data Independent Acquisition Mass Spectrometry (DIA-MS). Thousands of differentially expressed proteins (DEPs) changed over 12 weeks of treatment. Network analysis showed DEPs could interact and induce transformation in matrix components, metabolic regulation, and immune response. PRM analysis suggested S100s, STAT1, KRT2, TYMP, SOD2, HSP90AB1, TFRC, and COL5A1 were the most significantly changed proteins in both groups. There is a positively association between the psoriasis area and severity index (PASI) score and three proteins (TFRC, IMPDH2, KRT2). Our study suggests that inhibition of IL-17A and TNF-α can induce multiple molecules change in psoriatic lesions and overlapping effect on immune response and proces
2022-10-20 | PXD037579 | iProX
Project description:In psoriasis lesions, a diverse mixture of cytokines is upregulated which influence each other generating a complex inflammatory situation. Although this is the case, the inhibition of Interleukin-17A (IL-17A) alone showed unprecedented clinical results in patients, indicating that IL-17A is a critical inducer of psoriasis pathogenesis. To elucidate IL-17A-driven keratinocyte-intrinsic signaling pathways, we treated monolayers of normal human epidermal keratinocytes in vitro with a mixture of 6 cytokines (IL-17A, TNF-a, IL-17C, IL-22, IL-36g and IFN-g) involved in psoriasis, to mimic the inflammatory milieu in psoriasis lesions. Microarray and gene set enrichment analysis revealed that this cytokine mixture induced similar gene expression changes with the previous transcriptome studies using psoriasis lesions. Importantly, we identified a set of IL-17A-regulated genes in keratinocytes, which recapitulate typical psoriasis genes exemplified by DEFB4A, S100A7, IL19 and CSF3, based on differences in the expression profiles of cells stimulated with 6 cytokines versus cells stimulated with only 5 cytokines lacking IL-17A. Furthermore a specific IL-17A-induced gene, NFKBIZ, which encodes IkappaB-zeta, a transcriptional regulator for NF-kappaB, was demonstrated to have a significant role for IL-17A-induced gene expression. Thus, we present novel in vitro data from normal human keratinocytes that would help elucidating the IL-17A-driven keratinocyte activation in psoriasis. Cytokine mixture-induced gene expression in primary normal human epidermal keratinocytes (NHEKs) was measured at 24 hours after exposure. NHEKs were exposed to the combination of selected six cytokines (IL-17A: 100 ng/ml, TNF-a: 10 ng/ml, IFN-g: 10 ng/ml, IL-17C: 100 ng/ml, IL-22: 100 ng/ml, IL-36g: 500 ng/ml) , or to the different combinations of five of the six cytokines (in total, 7 different treatments and one untreated control). No replicate experiments were conducted.
2016-03-08 | E-GEOD-77719 | biostudies-arrayexpress