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The pathogenesis of psoriasis is characterized by dysregulated post-translational modifications, with particular emphasis on fucosylation-a glycosylation process mediated by fucosyltransferases (FUTs). Keratin 17 (K17), overexpressed in psoriatic keratinocytes, drives inflammation and proliferation, but its interplay with fucosylation remains unclear. This study aimed to elucidate the role of fucosylation in psoriasis, specifically focusing on the regulation of K17 stability by FUT11.Methods
To investigate fucosylation dynamics, we employed single-cell RNA sequencing (scRNA-seq) to analyze N-glycan biosynthesis activity in psoriatic versus healthy keratinocytes. Fucosylation levels were assessed in human and murine psoriatic lesions, as well as in cytokine-stimulated keratinocytes, using Aleuria aurantia lectin (AAL). An imiquimod (IMQ)-induced psoriasis-like mouse model and primary keratinocytes treated with psoriasis-associated cytokines (Pso-Mix) (IL-17, TNF-α, IL-1α, OSM and IL-22) were utilized to evaluate the effects of 2-fluorofucose (2-FF) and FUT11 siRNA. We further explored the mechanisms regulating K17 stability through immunoprecipitation, ubiquitination assays, and cycloheximide chase experiments.Results
Our findings revealed that psoriatic keratinocytes exhibited elevated levels of fucosylation, which correlated with upregulation of FUT11. Administration of 2-FF or silencing FUT11 significantly attenuated IMQ-induced inflammation, as evidenced by reductions in epidermal thickness, immune cell infiltration, and the expression of pro-inflammatory mediators such as IL-17A and CCL20. We demonstrated that FUT11 mediates α-1,3-fucosylation of K17, stabilizing it through K63-linked ubiquitination facilitated. Notably, silencing FUT11 disrupted the interaction between ubiquitination and fucosylation, leading to accelerated K17 degradation and a subsequent decrease in keratinocyte proliferation.Conclusions
Our results indicate that FUT11-driven fucosylation is integral to the stabilization of K17 via K63 ubiquitination, thereby perpetuating psoriatic inflammation. Targeting FUT11 or inhibiting fucosylation with 2-FF presents a novel therapeutic strategy for psoriasis management. This study highlights the critical interplay between glycosylation and ubiquitination in the pathophysiology of psoriasis, positioning FUT11 and K17 as pivotal targets for intervention.Weiterlesen
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Psoriasis is a chronic immune-mediated inflammatory disease. Systemic therapy is usually applicable to patients who have failed topical treatment or phototherapy, but the value of early systemic therapy remains unclear.Purpose
This study aimed to evaluate the impact of disease duration on the clinical efficacy and patients reported outcomes in moderate to severe psoriasis patients treated with systemic agents.Methods
Our research was based on the SPEECH, an observational, prospective, multicenter registry. Adult patients with moderate to severe psoriasis receiving systemic therapy (including biologics, methotrexate or acitretin) were divided into groups based on disease duration: <2 years, 2~10 years, and ≥10 years. The clinical efficacy was assessed using PASI (Psoriasis Area and Severity Index), BSA (Body Surface Area), PGA (Physician Global Assessment). The Dermatology Life Quality Index (DLQI), PtGA (Patient Global Assessment) and the Hospital Anxiety and Depression Scale (HADS) were used to assess the patients reported outcomes. The treatment outcomes were analyzed at 3 months and 6 months. Using multiple logistic regression to analyze the differences between patients with different disease duration, and conducting subgroup analysis and sensitivity analysis to test the robustness of the research results.Results
A total of 1908 patients who met the criteria were included in the analysis. After 3 months of treatment, the PASI75 response rates for the three groups of patients (<2 years, 2-10 years, and ≥10 years) were 55%, 55% and 60%, respectively all p value >0.05. No significant differences were observed among the three groups in the rates of achieving BSA <1/3, PGA 0/1, DLQI 0/1, PtGA 0/1, HADS-A = 0, and HADS-D = 0. Notably, these outcomes still showed no significant differences at 6 months. Subgroup and sensitivity analyses also yielded consistent results.Conclusion
Disease duration does not significantly affect clinical efficacy or patients reported outcomes in patients with moderate-to-severe psoriasis receiving systemic therapy. These results indicate that early systemic therapy does not improve treatment outcomes in real clinical settings, thereby supporting the continued efficacy of step-up treatment strategy and providing novel insights into clinical practice management.Weiterlesen
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Secukinumab, an interleukin-17 A (IL-17 A) inhibitor, is an approved treatment for psoriasis, but effects on the hypothalamic pituitary adrenal (HPA) axis are unknown.Methods
In a 16-week randomized controlled trial, 105 patients with psoriasis received secukinumab at either 300 or 75 mg. Plasma levels of IL-17 A, cortisol, adrenocorticotropic hormone, prolactin, dehydroepiandrosterone and perceived stress using Perceived Stress Scale (PSS-10) were measured at baseline and every four weeks. Treatment response was assessed using Psoriasis Area and Severity Index (PASI).Results
Both dosage groups showed significant increases in IL-17 A and cortisol, with no differences between groups. Cortisol increased by approximately 33 %, indicating activation of HPA axis. Changes in cortisol did not correlate with PASI. PSS-10 inversely correlated with cortisol at baseline, and shifted positive during follow-up.Conclusion
Secukinumab treatment in psoriasis is accompanied by HPA axis activation. Further studies are needed to determine the duration, mechanisms, and magnitude of this activation.Weiterlesen
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As biologic therapy is increasingly being utilized in the treatment of paediatric psoriasis, we aim to perform a systematic review and network meta-analysis to compare the efficacy and safety of available biologic treatments for moderate to severe paediatric plaque psoriasis.Methods
Relevant randomized controlled trials (RCTs) were searched for in PubMed, Embase, Cochrane CENTRAL and clinicaltrials.gov. We performed a fixed-effects frequentist network meta-analysis (NMA) with the surface under the cumulative ranking curve (SUCRA) calculated for and mean ranking calculated. The main outcomes of interest were a ≥75% improvement in PASI score (PASI75), ≥90% improvement in PASI score (PASI90), 100% improvement in PASI score (PASI100), CDLQI score of 0/1 (CDLQI 0/1) at weeks 12-16 and safety outcomes at 12-20 weeks. Point probabilities of response were also calculated, presented as absolute risk differences per 1000 patients with their 95% CIs compared to placebo.Results
Seven RCTs comprising 1016 psoriasis patients were included. Compared to placebo, all biologic therapies exhibited a significantly higher PASI90 and PASI75 response. Based on the SUCRA, Ixekizumab ranked highest in achieving the PASI100 (SUCRA: 0.9, Mean Rank: 1.8) response. Secukinumab high dose ranked the best for PASI90 (SUCRA: 0.8, Mean Rank: 3.0). For the CDLQI 0/1 (SUCRA: 0.8, Mean Rank: 2.2) response and the PASI75 (SUCRA: 0.9, Mean Rank: 2.2) response, standard dose Ustekinumab exhibited superior performance.Conclusion
All biologic agents (not including non-biologic comparators methotrexate and FAEs) were significantly superior to placebo, with no significant difference between individual biologic therapies, for the treatment of moderate-to-severe paediatric plaque psoriasis. Ixekizumab and Secukinumab demonstrated a trend towards a higher PASI90 response, while Ustekinumab showed a trend towards increased CDLQI and PASI75 responses. These findings highlight the need for better-powered trials in this population to determine the optimal treatment modality.Prospero number
CRD42023476983.Weiterlesen
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Inflammatory skin diseases including acne, atopic dermatitis, psoriasis, and psoriatic arthritis, and have become a major global public health concern. Diet's impact on inflammatory skin diseases has attracted significant attention. This study utilised the Mendelian randomization (MR) method to investigate the relationship between popular diets, such as low-calorie, vegetarian, and gluten-free diets, and several common inflammatory skin diseases.Methods
Our study employed five MR methods, including the inverse variance weighted (IVW), MR-Egger, simple mode, weighted median, and weighted mode. Sensitivity analysis was conducted to confirm the accuracy and reliability of the research findings.Results
The results revealed a positive causal relationship between low-calorie diets and the risk of psoriatic arthritis (odds ratio [OR]: 1.05; 95% confidence interval [CI]: 1.01-1.10; p = 0.008) but no significant association with other diseases. No significant association was observed between vegetarian or gluten-free diets and the diseases. The reliability of the conclusion was further validated through the MR-Egger regression, MR-PRESSO analysis.Conclusion
This study offers preliminary insights into the links between diet and inflammatory skin conditions, with future large-scale, multi-method research needed to validate these findings and inform dietary recommendations.Weiterlesen
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To determine which anatomical sites and which ultrasonographic entheseal lesions are best able to discriminate between spondyloarthritis (SpA) patients and healthy controls (HC).Methods
We included patients with psoriatic arthritis (PsA) and axial SpA (axSpA), from six Swiss hospital outpatient clinics, as well as HC. Participants completed quality of life and physical activity questionnaires and underwent a clinical examination of both joints and entheses, followed by a detailed musculoskeletal ultrasound examination including nine entheseal sites bilaterally. Entheses were scored according to the Outcome Measures in Rheumatology criteria, with an additional evaluation of bursae and power Doppler (PD) in the 2-5 mm zone.Results
Overall, 121 participants were included, including 41 with PsA (mean age in years (SD), percentage male: 54.5±11.0, 63.4%), 39 with axSpA (45.1±10.0, 51.3%) and 41 HC (43.9±10.9, 56.1%), with a total of 2178 entheses evaluated. The PsA and axSpA groups showed no significant differences regarding inflammatory markers or disease activity scores.In the univariable analysis, all ultrasonographic lesions at the enthesis showed a significant association with SpA vs HC. Only B-mode inflammatory lesions (OR=1.38, p=0.034) and active enthesitis (OR=4.45, p=0.030) retained this association in multivariable analyses. While 4/9 entheses were associated with SpA in univariable analyses, only the distal patellar ligament insertion remained significantly associated with SpA (OR=1.74, p=0.039) in multivariable analyses.Conclusion
To distinguish SpA patients from controls, the sonographic scoring system used should account not only for the presence of specific entheseal lesions (structural and inflammatory) but also for the individual site affected.Weiterlesen
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Psoriasis is a chronic, immune-mediated, inflammatory skin disease characterized by abnormal keratinocyte proliferation, in which M1 macrophage polarization plays a critical role. However, the specific biomarkers and mechanisms underlying macrophage polarization in psoriasis remain unclear.Methods
We analyzed the psoriasis dataset (GSE14905) to identify differentially expressed genes and applied weighted gene co-expression network analysis to identify key module genes. Macrophage polarization-related (MPR) genes were extracted from the Rummagene database, and MPR genes in psoriasis were identified through Venn analysis. Functional enrichment analysis (GO/KEGG) revealed associated pathways, while six CytoHubba algorithms determined hub genes, with diagnostic potential assessed via ROC curves. Single-gene GSEA further explored biological functions, and single-cell sequencing analysis was performed. Finally, the expression of hub genes and M1 macrophage markers (CD80/CD86) was experimentally validated in psoriasis mouse models.Results
Six hub genes (ISG15, RSAD2, IFIT3, OASL, GBP1, and IFIT1) were identified through cytoHubba algorithms. Functional enrichment analysis revealed significant associations between psoriasis-associated macrophage polarization and the RIG-I-like receptor, NOD-like receptor, and cAMP signaling pathways. Experimental validation verified the increased expression of these hub genes and M1 macrophage markers in LPS-stimulated RAW264.7 murine macrophages and IMQ-induced psoriasis animal models.Conclusion
Our findings suggest that six interferon-responsive genes (ISG15, RSAD2, IFIT3, OASL, GBP1, and IFIT1) could serve as potential biomarkers for M1 macrophage polarization in psoriasis. Targeting macrophage polarization through IFN pathway inhibition may offer novel therapeutic strategies, particularly for patients with prominent IFN signatures refractory to conventional treatments.Weiterlesen
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Although biologic and systemic therapies have advanced psoriasis management, real-world evidence guiding individualized treatment remains limited. In particular, the influence of body size and metabolic parameters on disease severity and treatment response is underexplored.Objective
To investigate the associations of body mass index (BMI), basal metabolic rate (BMR), body surface area (BSA), and body weight with baseline psoriasis severity and therapeutic response across different treatment modalities.Methods
This multicenter, prospective study included 1955 patients from the Shanghai Psoriasis Effectiveness Evaluation CoHort (SPEECH) and 1663 patients for longitudinal follow-up. Multivariable regression models were used to examine the associations between body size/metabolic parameters and the baseline psoriasis area and severity index (PASI) scores, as well as PASI-based treatment responses at Week 12 and Week 20. Stratified analyses by treatment type and receiver operating characteristic curve analysis were conducted to assess predictive performance.Results
All four parameters were positively associated with baseline PASI scores (FDR-adjusted P < 0.05). Prospectively, elevated BMI, BMR, BSA, and body weight were significantly associated with reduced likelihood of achieving PASI 75/90/100, and lower percentage reduction in PASI score at both time points. These associations were particularly pronounced in patients receiving biologic therapies. In the ustekinumab subgroup, body composition showed enhanced predictive accuracy for high-level PASI responses.Conclusion
Elevated BMI, BSA, body weight, and BMR are associated with more severe psoriasis and diminished treatment efficacy, especially those treated with biologics. These findings underscore the need for personalized dosing strategies in biologic therapy, especially for fixed-dose agents like ustekinumab.Weiterlesen
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To identify new targets for protein-based treatments in psoriasis and evaluate the possible negative impacts of these druggable proteins.Methods
We carried out an extensive analysis of the entire set of proteins in the blood (proteome-wide) to determine if there are causal links between certain blood proteins and the likelihood of developing psoriasis. The proteins were selected from the UK Biobank Pharma Proteomics Project (UKBPPP) database, which includes genetic data for 2,940 different blood proteins. We obtained the cis-expression quantitative trait locus (cis-eQTL) of druggable genes from eQTLGen Consortium as exposure and the genome-wide association study (GWAS) of psoriasis.Results
Our research discovered a strong genetic link between plasma APOF, ATP6V1G2, IFNLR1, CRELD1, PRSS8, and TNF proteins and a higher chance of having psoriasis. These proteins share genetic variations associated with psoriasis (PPH3+PPH4>0.8). The ROC curves derived from these protein quantity trait loci (pQTLs) demonstrate that they can distinguish between individuals with psoriasis and those without. The druggable gene analysis showed that simvastatin is related to TNF based on the Drug SIGnatures DataBase webtool.Conclusion
Our study has explored the causal relationships between six blood proteins and psoriasis, offering a detailed insight into potential therapeutic targets. Among them, simvastatin might have an effect on psoriasis via TNF.Weiterlesen
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Secondary failure to biologic disease-modifying antirheumatic drugs (bDMARDs) is challenging and contributes to the complexity of managing psoriatic arthritis (PsA). We aimed to define the frequency and incidence of this phenomenon in PsA and identify the risk factors for its occurrence.Methods
We retrieved data on patients with PsA from our single-center, specialized-care, prospective observational cohort who initiated and remained on bDMARDs for ≥ 1 year after clinic enrollment between 2000 and 2023. We defined response to therapy at the 1-year visit (baseline) as achievement of ≥ 40% reduction in the swollen joint count (SJC) and either ≥ 50% reduction in Psoriasis Area and Severity Index (PASI) or PASI ≤ 2. We defined secondary failure as the inability to maintain response criteria or as the clinician's judgment of loss of effectiveness. To examine factors associated with secondary failure, we fitted Cox regression models.Results
Of 482 patients included in the study, 264 (54.8%) were responders at 1 year. Of these, 94 (35.6%) developed secondary failure at a median of 1.6 (IQR 0.7-3.8) years from response. In the multivariable model, higher SJC (hazard ratio [HR] 1.39, 95% CI 1.05-1.84) and PASI (HR 1.14, 95% CI 1.01-1.29) at baseline were associated with secondary failure. Tumor necrosis factor inhibitors (TNFi) vs other bDMARD use (HR 0.39, 95% CI 0.18-0.88), initiation as first-line bDMARD (HR 0.48, 95% CI 0.25-0.91), and treatment initiation during more recent calendar years (HR 0.34, 95% CI 0.12-0.98) were associated with less secondary failure.Conclusion
Secondary failure to bDMARD is common in PsA and may be influenced by both disease- and therapy-related factors.Weiterlesen
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To estimate the prevalence of psoriatic arthritis (PsA) and associated fac-tors in patients with moderate-to-severe psoriasis. Methods:
Retrospective, single-center study of a cohort of psoriasis patients in stand-ard follow-up in a dermatology department from July 2008 to January 2024. Patients ≥18 years with moderate-to-severe psoriasis were included and classified into 3 groups according to the treatment received: group 1, biologics or small molecules with or without conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs); group 2, only csDMARDS; and group 3, non-pharmacological treatments. Demographic and clinical variables were collected. The prevalence of PsA was estimated with its 95% confidence interval (CI). The cumulative incidence of PsA was analyzed across groups, and logistic regression models were built. Results:
The study population comprised 308 patients (67.2%, 22.7%, 10% in groups 1, 2, and 3, respectively). Dif-ferences between the groups were observed in severity of psoriasis, weight, smoking status, and dyslipidemia (p< 0.05). The prevalence of PsA was 11.7% (95% CI, 8.1-15.3), with most patients in group 1. This group had a high-er risk of PsA following diagnosis of psoriasis or initiation of treatment. Belonging to groups 2 and 3 had a smaller effect than belonging to group 1 in the development of PsA; nail involvement and obstructive sleep apnea (OSA) were associated with development of PsA (p< 0.05). Conclusions:
The prevalence estimate was lower than previous estimates, probably owing to the increased use of biologics. Not requiring biologics for disease control had less effect on development of PsA. Nail involvement and OSA were associated with PsA.Weiterlesen
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