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Abstract. Background:. There is a need for effective and safe therapies for psoriasis that provide sustained benefits. The aim of this study was to assess the efficacy and safety of tildrakizumab, an anti-interleukin-23p19 monoclonal antibody, for treating moderate-to-severe plaque psoriasis in Chinese patients. Methods:. In this multi-center, double-blind, phase III trial, patients with moderate-to-severe plaque psoriasis were enrolled and randomly assigned (1:1) to receive subcutaneous tildrakizumab 100 mg or placebo at weeks 0 and 4. Patients initially assigned to placebo were switched to receive tildrakizumab at weeks 12, 16, and every 12 weeks thereafter. Patients in the tildrakizumab group continued with tildrakizumab at week 16, and every 12 weeks until week 52. The primary endpoint was the Psoriasis Area and Severity Index (PASI 75) response rate at week 12. Results:. At week 12, tildrakizumab demonstrated significantly higher PASI 75 response rates (66.4% [73/110] vs. 12.7% [14/110]; difference, 51.4% [95% confidence interval (CI), 40.72, 62.13]; P

Abstract Background: Primary cutaneous CD4+ small/medium-sized pleomorphic T-Cell lymphoproliferative disorder (PC-SMTLD) has been considered as a controversial dermatological disease that has been included in cutaneous T-cell lymphoma group, presenting most commonly as a solitary nodule and/or plaque with a specific and characteristic head and neck predilection. Due to the considerable overlap between PC-SMTLD and pseudolymphoma (PL), the differential diagnosis is often challenging. Methylation of DNA at position 5 of cytosine, and the subsequent reduction in intracellular 5-hydroxymethylcytosine (5-hmC) levels, is a key epigenetic event in several cancers, including systemic lymphomas. However, it has rarely been studied in cutaneous lymphomas. Objectives: The authors aimed to explore the role of differential 5-hmC immunostaining as a useful marker to distinguish PC-SMTLD from PL. Methods: Retrospective case series study with immunohistochemical and immunofluorescence analysis of 5-hmC was performed in PL and PC-SMTLD. Results: Significant decrease of 5-hmC nuclear staining was observed in PC-SMTLD when compared with PL (p

BackgroundsObservational studies have shown that cigarette smoking is inversely associated with risk of rosacea, However, it remains uncertain whether this association is causal or it is a result of reverse causation, and whether this association is affected by drinking behaviors.MethodsThis study utilized the summary-level data from the largest genome-wide association study (GWAS) for smoking, alcohol consumption, and rosacea. The objective was to investigate the effect of genetically predicted exposures to smoking and alcohol consumption on the risk of developing rosacea. Two-sample bidirectional Mendelian randomization (MR) was applied, accompanied by sensitive analyses to validate the robustness of findings. Furthermore, multivariable MR was conducted to evaluate the direct impact of smoking on rosacea.ResultsA decreased risk of rosacea was observed in individuals with genetically predicted lifetime smoking [odds ratio (OR)MR − IVW = 0.53; 95% confidence interval (CI), 0.318–0.897; P = 0.017], and number of cigarettes per day (ORMR − IVW = 0.55; 95% CI, 0.358–0.845; P = 0.006). However, no significant associations were found between initiation of regular smoking, smoking cessation, smoking initiation, alcohol consumption and rosacea. Reverse MR analysis did not show any associations between genetic liability toward rosacea and smoking or alcohol drinking. Importantly, the effect of lifetime smoking and the number of cigarettes per day on rosacea remained significant even after adjusting for alcohol consumption in multivariable MR analysis.ConclusionSmoking was causally related to a lower risk of rosacea, while alcohol consumption does not appear to be associated with risk of rosacea.

Abstract Atopic dermatitis (AD) is a chronic skin disease caused by skin immune dyshomeostasis and accompanied by severe pruritus. Although oxidative stress and mechanical scratching can aggravate AD inflammation, treatment targeting scratching is often overlooked, and the efficiency of mechano-chemically synergistic therapy remains unclear. Here, we find that enhanced phosphorylation of focal adhesion kinase (FAK) is associated with scratch-exacerbated AD. We then develop a multifunctional hydrogel dressing that integrates oxidative stress modulation with FAK inhibition to synergistically treat AD. We show that the adhesive, self-healing and antimicrobial hydrogel is suitable for the unique scratching and bacterial environment of AD skin. We demonstrate that it can scavenge intracellular reactive oxygen species and reduce mechanically induced intercellular junction deficiency and inflammation. Furthermore, in mouse AD models with controlled scratching, we find that the hydrogel alleviates AD symptoms, rebuilds the skin barrier, and inhibits inflammation. These results suggest that the hydrogel integrating reactive oxygen species scavenging and FAK inhibition could serve as a promising skin dressing for synergistic AD treatment.

IntroductionThe 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.MethodsIn our study, we compared the 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 first used to characterize bacterial gut microbial communities and related functional changes in the AT group.ResultsWe found that the diversity and structure of the microbial community in the AT group were significantly changed compared to those in the BT group and the H group. The 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 the gut microbiome with functional alteration. There were different KEGG pathways, such as the downregulated cardiovascular diseases pathway and the upregulated infectious diseases in the AT group. By metagenomic analysis, the metabolic functional pathway was changed after secukinumab therapy.DiscussionIt seems that gut microbiota investigation during biologic drug treatment is useful for predicting the efficacy and risks of drug treatment in disease.

Mast cell (MC) activation is implicated in the pathogenesis of multiple immunodysregulatory skin disorders. Activation of an IgE-independent pseudo-allergic route has been recently found to be mainly mediated via Mas-Related G protein-coupled receptor X2 (MRGPRX2). Ryanodine receptor (RYR) regulates intracellular calcium liberation. Calcium mobilization is critical in the regulation of MC functional programs. However, the role of RYR in MRGPRX2-mediated pseudo-allergic skin reaction has not been fully addressed. To study the role of RYR in vivo, we established a murine skin pseudo-allergic reaction model. RYR inhibitor attenuated MRGPRX2 ligand substance P (SP)-induced vascular permeability and neutrophil recruitment. Then, we confirmed the role of RYR in an MC line (LAD2 cells) and primary human skin-derived MCs. In LAD2 cells, RYR inhibitor pretreatment dampened MC degranulation (detected by β-hexosaminidase retlease), calcium mobilization, IL-13, TNF-α, CCL-1, CCL-2 mRNA, and protein expression activated by MRGPRX2 ligands, namely, compound 48/80 (c48/80) and SP. Moreover, the inhibition effect of c48/80 by RYR inhibitor was verified in skin MCs. After the confirmation of RYR2 and RYR3 expression, the isoforms were silenced by siRNA-mediated knockdown. MRGPRX2-induced LAD2 cell exocytosis and cytokine generation were substantially inhibited by RYR3 knockdown, while RYR2 had less contribution. Collectively, our finding suggests that RYR activation contributes to MRGPRX2-triggered pseudo-allergic dermatitis, and provides a potential approach for MRGPRX2-mediated disorders.

STAG2 is a core subunit of the cohesin complex involved in DNA looping, but its transcriptional targets are largely unknown. Here the authors show STAG2 controls the 3D chromatin structure at the IRF9 locus to restrict IRF9 expression. Loss of STAG2 results in IRF9 activation, which in turn upregulates PD-L1 expression in cancer cells, suggesting a tumor suppressor function in immune evasion.

Summary Trichophyton rubrum is responsible for the majority of dermatophytosis. Current systemic and topical antifungals against dermatophytosis are often tedious and sometimes unsatisfactory. Antimicrobial photodynamic therapy (aPDT) is a non‐invasive alternative suitable for the treatment of superficial fungal infections. This work investigated the photodynamic inactivation efficacy and effects of aloe‐emodin (AE), a natural photosensitizer (PS) against T. rubrum microconidia in vitro, and evaluated the treatment effects of AE‐mediated aPDT for T. rubrum‐caused tinea corporis in vivo and tinea unguium ex vivo. The photodynamic antimicrobial efficacy of AE on T. rubrum microconidia was evaluated by MTT assay. The inhibition effect of AE‐mediated aPDT on growth of T. rubrum was studied. Intracellular location of AE, damage induced by AE‐mediated aPDT on cellular structure and surface of microconidia and generation of intracellular ROS were investigated by microscopy and flow cytometry. The therapeutic effects of AE‐mediated aPDT against dermatophytosis were assessed in T. rubrum‐caused tinea corporis guinea pig model and tinea unguium ex vivo model. AE‐mediated aPDT effectively inactivated T. rubrum microconidia in a light energy dose‐dependent manner and exhibited strong inhibitory effect on growth of T. rubrum. Microscope images indicated that AE is mainly targeted to the organelles and caused damage to the cytoplasm of microconidia after irradiation through generation of abundant intracellular ROS. AE‐mediated aPDT demonstrated effective therapeutic effects for T. rubrum‐caused tinea corporis on guinea pig model and tinea unguium in ex vivo model. The results obtained suggest that AE is a potential PS for the photodynamic treatment of dermatophytosis caused by T. rubrum, but its permeability in skin and nails needs to be improved.

Abstract Background Psoriasis is an inflammatory skin disease associated with multiple comorbidities and substantially diminishes patients’ quality of life. The gut microbiome has become a hot topic in psoriasis as it has been shown to affect both allergy and autoimmunity diseases in recent studies. Our objective was to identify differences in the fecal microbial composition of patients with psoriasis compared with healthy individuals to unravel the microbiota profiling in this autoimmune disease. Results We collected fecal samples from 30 psoriasis patients and 30 healthy controls, sequenced them by 16S rRNA high-throughput sequencing, and identified the gut microbial composition using bioinformatic analyses including Quantitative Insights into Microbial Ecology (QIIME) and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). Our results showed that different relative abundance of certain bacterial taxa between psoriasis patients and healthy individuals, including Faecalibacterium and Megamonas, were increased in patients with psoriasis. It’s also implicated that many cytokines act as main effect molecules in the pathology of psoriasis. We selected the inflammation-related indicators that were abnormal in psoriasis patients and found the microbiome variations were associated with the level of them, especially interleukin-2 receptor showed a positive relationship with Phascolarctobacterium and a negative relationship with the Dialister. The relative abundance of Phascolarctobacterium and Dialister can be regard as predictors of psoriasis activity. The correlation analysis based on microbiota and Inflammation-related indicators showed that microbiota dysbiosis might induce an abnormal immune response in psoriasis. Conclusions We concluded that the gut microbiome composition in psoriasis patients has been altered markedly and provides evidence to understand the relationship between gut microbiota and psoriasis. More mechanistic experiments are needed to determine whether the differences observed in gut microbiota are the cause or consequences of psoriasis and whether the relationship between gut microbiota and cytokines was involved.

Abstract Background Nakajo-Nishimura syndrome (NNS) is an autosomal recessive heredity disorder, one of a spectrum of autoinflammatory diseases named proteasome-associated autoinflammatory syndrome (PRAAS) caused by mutations of PSMB8 gene. NNS is characterized by pernio-like skin rashes, intermittent fever, and long clubbed fingers and toes with joint contractures, partially with progressive lipomuscular atrophy, emaciation, hepatosplenomegaly and basal ganglion calcification. Case presentation We presented a sporadic case of NNS with compound heterozygous mutations in the PSMB8 gene. The 4-year-old boy was affected by progressive erythematous plaques on his nose and gradually involved hands and feet later with characteristic appearance of long clubbed fingers. The repetitive periodic intermittent fever was recorded. By gene sequencing, novel compound heterozygous mutations c.373C > T (p.R125C) and c.355G > A (p.D119N) in the PSMB8 gene were found. The patient responded well to low dosage of oral methylprednisolone. Conclusions We reported novel compound heterozygous mutations in PSMB8 in a sporadic Chinese NNS patient.

Infectious dermatological diseases caused by Malassezia furfur are often chronic, recurrent, and recalcitrant. Current therapeutic options are usually tedious, repetitive, and associated with adverse effects. Alternatives that broaden the treatment options and reduce side effects for patients are needed. Antimicrobial photodynamic therapy (aPDT) is an emerging approach that is quite suitable for superficial infections. The aim of this study is to investigate the antimicrobial efficacy and effect of aPDT mediated by haematoporphyrin monomethyl ether (HMME) and aloe emodin (AE) on clinical isolates of M. furfur in vitro. The photodynamic antimicrobial efficacy of HMME and AE against M. furfur was assessed by colony forming unit (CFU) assay. The uptake of HMME and AE by M. furfur cells was investigated by fluorescence microscopy. Reactive oxygen species (ROS) probe and flow cytometry were employed to evaluate the intracellular ROS level. The effect of HMME and AE-mediated aPDT on secreted protease and lipase activity of M. furfur was also investigated. The results showed that HMME and AE in the presence of light effectively inactivated M. furfur cells in a photosensitizer (PS) concentration and light energy dose-dependent manner. AE exhibited higher antimicrobial efficacy against M. furfur than HMME under the same irradiation condition. HMME and AE-mediated aPDT disturbed the fungal cell envelop, significantly increased the intracellular ROS level, and effectively inhibited the activity of secreted protease and lipase of M. furfur cells. The results suggest that HMME and AE have potential to serve as PSs in the photodynamic treatment of dermatological diseases caused by M. furfur, but further ex vivo or in vivo experiments are needed to verify that they can meet the requirements for clinical practice.

Chronic urticaria (CU) is a debilitating skin disease that lasts for more than 6 weeks with wheals and/or angioedema, including chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU). In China, the prevalence of this disease is high, more than 1%, and on the rise. CU has a major impact on the quality of life (QoL) of patients who frequently experience sleep disturbance, depression, and anxiety. Nearly one-third of patients with CSU, in China, are resistant to second-generation H1-antihistamines (sgAHs), even at a fourfold dose (second line; off-label). Omalizumab is approved for the treatment of CSU treatment in Europe and shows remarkable efficacy and safety. In China, regulatory approval for the use of omalizumab is pending, and its use in clinical practice varies widely. Consensus on omalizumab CU treatment in China is urgently needed. The aim of this article is to propose a practical omalizumab treatment algorithm for the management of antihistamine-resistant CSU and CIndU in adults and special population including children and adolescents, and pregnant or breast feeding women, to guide daily clinical practice in China. In the development of this consensus, an expert group including mainly dermatologists, allergists, but also pulmonologists, ENTs, immunologists, and pediatricians in Allergic Disease Prevention and Control Committee, Chinese Preventive Medicine Association, reviewed the existing evidence and developed consensus on the use of omalizumab in CU patients from China. The goal of this consensus is to assist clinicians in making rational decisions in the management of refractory CU with omalizumab. The key clinical questions covered by the treatment algorithm are: 1) Omalizumab treatment routine strategy in both CSU and CIndU patients; 2) Recommended dose and treatment duration for different age stratification; 3) Treatment duration for CU patients with other allergic comorbidities; 4) Recommendation on omalizumab stopping strategy.

Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disorder in the elderly. Systemic and topical use of glucocorticoids and immunosuppressants has been shown to be effective in most patients. However, refractory BP patients are challenged to clinicians with severe clinical symptoms, resistance to treatment, and high relapse rate. How to predict and assess the refractory and severity of bullous pemphigoid is the key issue in clinical practice, and the urgent need for precision medicine in refractory patients is driving the search for biomarkers and biologics. Recently, some biomarkers, such as the level of specific autoantibodies and released cytokines, have been proposed as the potential parameters to reflect the disease severity and predict the treatment response and relapse of refractory BP. Moreover, new biologics targeting pathogenic antibodies, complement, Th2 axis, eosinophils, and Th17 axis have shown potent efficacy on refractory BP. Here, we review the literature and give an overview of emerging biomarkers and therapeutic strategies for refractory bullous pemphigoid to improve the prognosis of the patient.

Porokeratosis (PK) is defined as hyperpigmented macules or patches with a distinctive, ridge-like hyperkeratotic border which is histologically characterized by a cornoid lamella. Here, we report two cases of linear porokeratosis which converted to multiple cutaneous squamous cell carcinoma after long history progression. In addition, patient 2 was accompanied by secondary dermal amyloid deposits, which was rare reported.

Basal cell carcinoma (BCC) is the most prevalent epidermal cancerous neoplasm. Previous studies have reported the noninvasive, cost-effective, and localized photodynamic therapy (PDT) approach to BCC treatment. This study investigated the photodynamic effects of aloe-emodin (AE), a natural anthraquinone photosensitizer (PS), on proliferation and apoptosis of BCC TE 354.T cell line. To evaluate the effects of AE-mediated PDT, we used various concentrations of AE (0, 2.5, 5, and 10 μM) and white light energy (0, 12, 24, and 36 J/cm2). CCK-8 assay was used to analyse cell viability following AE-mediated PDT. The cell death rate and reactive oxygen species (ROS) were assessed by flow cytometry. Western blotting was used to determine the effects of AE-mediated PDT on the apoptotic proteins, Akt, and MAPK pathways. AE-mediated PDT inhibited tumorigenic cell proliferation, consequently enhancing apoptosis in AE and PDT concentration and dose-dependent manner, respectively. Significantly increased TE 354.T cell apoptosis and intracellular ROS production were both observed after AE-mediated PDT. Following the AE-mediated PDT, cytochrome and antitumor p53 were elevated; however expression of Bcl-2 was significantly decreased. Significant caspase 3 elevation post-AE-mediated PDT suggested intrinsically driven apoptosis. Additionally, AE-mediated PDT significantly suppressed NF-κB, Akt, and ERK pathways while JNK expression was significantly increased. AE-mediated PDT induced TE 354.T cell apoptosis through the intracellular generation of ROS. Akt, ERK, and JNK all play various roles in ensuring successful TE 354.T tumor cell apoptosis.

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Hyper IgE syndrome (HIES) is a rare disorder characterized by eczema, recurrent infections of the skin and lungs, typically with Staphylococcus aureus, Candida albicans and certain viruses, and elevated levels of serum IgE. Other clinical manifestations include characteristic facies (prominent forehead, broad nasal bridge and facial asymmetry), chronic eczematous dermatitis, retained primary dentition, recurrent pathological fractures, hyper-extensibility and scoliosis. The central nervous system (CNS) involvement in HIES has been rarely reported. Here we presented a case of HIES with rare associations of epilepsy in a young patient to raise awareness for this disorder.

Background: The Q-switched neodymium-doped yttrium aluminum garnet (QS Nd:YAG) laser has a significant effect in treating nevus of Ota, but there is lack of a retrospective study about the characteristics of efficacy. Aims and Objectives: To retrospectively analyze the correlation between the clinical characteristics and efficacy, complications, recurrence of QS Nd:YAG laser in treating nevus of Ota. Materials and Methods: One hundred and seventy-one Chinese patients (144 female, 27 male) of nevus of Ota were treated with the 1064-nm QS Nd:YAG laser. All cases were treated with fluencies of 4–8 J/cm2 and a spot size of 2–4 mm. Clinical photographs were taken before every treatment and patients were followed up by their clinicians. Results: One hundred and forty-five patients (84.8%) acquired more than 75% improvement with an average of 4.6 sessions. The treatment effect has no significant correlation with sex (P > 0.05). The blue-black and brown lesions improved more than the light-brown (P < 0.05). Hyperpigmentation affected two (1.2%) of the patients and hypopigmentation affected one patient (0.6%). No other adverse effect was observed. Recurrence was seen in two patients (1.2%). Conclusion: The 1064-nm QS Nd:YAG laser is effective with rare complications and recurrence in the treatment of nevus of Ota. The efficacy correlated with lesion color, which is meaningful to estimate the prognosis.