The efficacy and safety of brodalumab in Japanese patients with palmoplantar pustulosis (PPP) were demonstrated during the 16-week double-blind phase of a randomized controlled trial. However, long-term data are unavailable. To assess the efficacy and safety of brodalumab 210 mg administered subcutaneously (SC) repeatedly until Week 68 in PPP patients with moderate or severe pustules/vesicles in an open-label extension study. In a multicentre, Phase 3, randomized, double-blind, placebo-controlled trial, Japanese adults having a diagnosis of PPP for ≥24 weeks, PPP Area Severity Index (PPPASI) of ≥12, PPPASI subscore of pustules/vesicles of ≥2 and inadequate response to therapy were included. Patients completing the double-blind phase with brodalumab 210 mg or placebo (1:1) SC once every 2 weeks (Q2W) for 16 weeks were invited to enter the open-label extension to receive brodalumab for the subsequent 52 weeks. By Week 68, 35 patients in the brodalumab group and 43 patients in the placebo-to-brodalumab group completed the study, with discontinuations (28 and 20 patients, respectively) primarily due to patient withdrawal. At Week 68, the mean ± SD improvement of the PPPASI total score from baseline was 23.83 ± 12.28 and 22.37 ± 13.09 in the brodalumab and placebo-to-brodalumab groups, respectively. Continued improvement or trend for improvement was seen in the secondary endpoints such as PPPASI 50/75/90 responses and Dermatology Life Quality Index. The incidence of adverse events was 849.3/100 person-years. Otitis externa had the highest incidence (44.0/100 person-years; Grade 1 or 2 only). Infection-related events were frequent but controllable. Brodalumab SC 210 mg Q2W administered for 68 weeks showed a long-term benefit to both dermatological and quality of life indices in these patients. It is expected to be used in appropriate patients, considering both safety risks and efficacy benefits. Palmoplantar pustulosis (PPP) is a difficult‐to‐treat, chronic skin disease. In PPP, pustules and vesicles keep reappearing on palms and/or soles. In 2011, ~0.01% to 0.05% of people in Western countries and 0.12% in Japan had PPP. It is more common in women, the elderly and smokers. We conducted a long‐term trial in Japan to treat PPP with brodalumab. Brodalumab is a human monoclonal antibody that works against IL‐17RA. We analysed the benefit and safety of brodalumab in PPP. In the first 16 weeks, 126 patients participated. Patients received brodalumab (210 mg dose every 2 weeks) or a placebo. Both groups had similar baseline characteristics. In total, 112 patients completed the 16‐week period. Results for the 16‐week period are published previously. Patients from both groups willing to continue were treated with brodalumab. Some patients dropped out due to various reasons. In total, 78 of 126 patients completed the 68‐week study. Of these, 35 were from the brodalumab‐only and 43 from the placebo‐to‐brodalumab group. At Week 68, mean improvement from baseline of 23.83 and 22.37, respectively, was seen in the PPPASI disease score. The proportion of patients showing 50%, 75% or 90% reduction in disease severity increased from Week 16 to Week 68. Dermatology Life Quality Index also showed continuous improvement. Some adverse events occurred. However, there were no deaths. Infection‐related events were frequent but generally controllable. We observed continuous improvement in the brodalumab‐only group. Also, we observed ‘catch‐up’ improvement in the placebo‐to‐brodalumab group. Overall skin scores and quality of life scores improved. Our results support long‐term benefit with brodalumab in PPP treatment.
Kindler syndrome (KS) or Kindler epidermolysis bullosa (KEB) is a rare genetic autosomal skin fragility disorder with photosensitivity and abnormal pigmentation, with patients also having an increased risk of developing cutaneous squamous cell carcinoma (cSCC). Gain a better understanding of the pathophysiology of KEB and the effects of UV radiation. We generated a K14CreERT2 Kindlin-1-/- SKH1 mouse which provides a valuable model to understand the complex interactions between keratinocytes and the skin environment following epidermal deletion of Kindlin-1 in adult mice. Proteomic analysis of mouse skin identified significant changes associated with an epithelial-to-mesenchymal transition (EMT) including the upregulation of several extracellular matrix (ECM) proteins comprising fibrillar collagens and matrix remodeling enzymes following deletion of Kindlin-1. Detailed analysis of collagen within the skin showed increased content and fiber alignment consistent with a more fibrotic environment. Mechanistically, we found increased TGFβ signaling and activation of dermal fibroblasts in Kindlin-1 deleted skin, highlighting the importance of paracrine signaling in the control of skin homeostasis by Kindlin-1. Kindlin-1 deletion led to profound suppression of gene expression of the antioxidant enzyme Gstp1 and exacerbated ultraviolet radiation (UVR) induced DNA damage consistent with increased TGFβ signaling and an inability of Kindlin-1 deleted skin to mount an effective protective response to UVR. This work offers insights into how Kindlin-1 loss alters skin homeostasis and induces a tumor-permissive environment.
The greatest burden of HIV infection is in sub-Saharan African countries. The burden of treatment failure among children living with HIV remains significantly high due to delayed diagnosis and antiretroviral therapy (ART) initiation, low ART adherence rate, virological non-suppression, and incidence of adverse drug reactions (ADRs) to ART, among other factors. Therefore, this systematic review aims to estimate the pooled prevalence of ADRs among HIV-positive pediatric patients on ART in sub-Saharan Africa, identify the types, and examine associated risk factors as documented in the literature. This review is based on a systematic and extensive search of PubMed, Scopus, CINAHL, Web of Science, and EBSCOHost. Data were extracted from the included studies using the data extraction form designed by the team. A meta-analysis was done using R statistics, version 4.3.2. A total of nine articles were included. The pooled estimate of ADRs among children on ART was statistically significant 26% (95% CI 0.15, 0.36; P-value < 0.001) with high heterogeneity. The types of ADRs reported in the included studies are gastrointestinal, dermatological, central nervous system, hematological, liver pathology, metabolic disorder, cardiovascular, and hormonal imbalance symptoms. Some of the factors associated with the occurrence of ADRs include treatment duration, the combination of ART used, sex, age, malnutrition, and compliance. The pooled prevalence of mortality among children on ART was statistically significant, with high heterogeneity. The review highlighted the prevalence and factors associated with ADRs in HIV-positive children on ART in the SSA countries. As the SSA countries battle to achieve the UNAIDS 95-95-95 targets in this vulnerable population, preliminary insights from this review can help inform policies on integrating spontaneous reporting of ADRs and pharmacovigilance into the service delivery component of pediatric ART. This intervention will support patient retention in care, as ADRs are a significant cause of medication non-adherence. Not applicable.
In accordance with the advancement of therapies for skin malignancies, the Japanese Dermatological Association and Japanese Skin Cancer Society updated guidelines for skin malignancies to reflect current clinical practices. Basal cell carcinoma (BCC) is one of the most ordinary malignant cutaneous tumors and its incidence continues to grow in many countries. Clinically, BCCs in East Asian populations are usually pigmented, and 88.3% of total BCCs in Japanese patients are pigmented. However, a low proportion of BCCs in Western populations are pigmented. Therefore, diagnosis and tumor border evaluation of BCCs in Western populations are relatively difficult. From these characteristics, clinical guidelines for East Asian BCCs should differ from those for Western BCCs. This revised Japanese clinical guideline for BCC was also undertaken by a committee comprising experts across relevant fields who meticulously reviewed and systematized a wide range of literature on BCC to develop comprehensive, evidence-based guidelines. Literature searches were conducted by the Japan Medical Library in accordance with the Minds Clinical Practice Guideline Creation Manual 2020, ver. 3.0. Four clinical questions (CQs) were established, and corresponding recommendation statements were provided for each CQ. There are about the reduced margin resection for pigmented BCCs, the radiotherapy for the recurrent BCCs, the topical immune response modifiers, and the systemic therapy using immune checkpoint inhibitors. This Japanese clinical guideline for BCC will help clinicians select suitable therapies for BCCs in East Asia.
Neurodermatitis is characterised by chronic itching and scratching. It greatly affects patients' quality of life, causing physical, emotional and social challenges. While dermatological treatments have improved, traditional therapies often fall short of meeting individual patient needs, especially in managing the persistent urge to scratch, which worsens the condition. The objective of this review study was to analyse the impact of tailored interventions on symptom reduction, particularly itching and excoriation. The research question formulation on PICO served as the foundation for the search approach. Key words were searched in different combinations from the popular databases Scopus, PubMed, Web of Science and Cochrane Library. Boolean operators (AND and OR and NOT) and keywords were employed in the search, to avoid oversaturating the data. Some 12 full-text articles were selected for the study. These findings provide encouraging evidence for the potential effectiveness of tailored approaches in managing neurodermatitis, in terms of reducing the symptoms of the urge to scratch. They emphasise the need for further research to validate and optimise these interventions. Adherence to treatment and high user satisfaction were prominent outcomes, with tailored interventions enhancing adherence. Interventions customised to individual patient needs, such as tailored therapeutic regimens, combination therapies, counselling and biologic treatments, are highly effective in reducing excoriation urges, improving skin healing and enhancing quality of life. These approaches foster better adherence and satisfaction among patients. Future research should aim to optimise these strategies and to bridge existing gaps, ultimately enhancing outcomes and quality of life for individuals with neurodermatitis.
Postexposure prophylaxis with doxycycline (Doxy-PEP) significantly reduces incidence of certain bacterial STIs in men who have sex with men (MSM) and individuals with recurrent STIs. We assessed knowledge, attitudes, and clinical experience regarding Doxy-PEP of dermatologists specialized in STI prevention, diagnosis, and treatment in Italy. A cross-sectional survey was conducted in March 2025 using a questionnaire to investigate knowledge of Doxy-PEP prescribing protocols and patient eligibility, perceptions of its efficacy against several STIs, personal experience in Doxy-PEP prescription and drawbacks, opinions on its future use. Thirty-six dermatologists participated. All knew about Doxy-PEP. The population most frequently considered eligible for Doxy-PEP was represented by MSM (69.4%). Respondents would prescribe Doxy-PEP after recent exposure (<72 hours) to chlamydia (58.3%), syphilis (50.0%), gonorrhea (25.0%), or multiple partnership (55.6%). Chemsex was indicated as the main risky behavior worth prescribing Doxy-PEP (69.4%). Approximately half of the respondents considered Doxy-PEP effective against chlamydia (47.2%), whereas only 14.3% and 2.8% were convinced of its efficacy against syphilis and gonorrhea, respectively. Only 19.4% of the respondents had prescribed Doxy-PEP, with no adverse events reported. Doxy-PEP failure was observed by 36.1% of the dermatologists. The main concerns included Neisseria gonorrhoeae resistance (91.7%), methicillin-resistant Staphylococcus aureus (MRSA) selection (91.7%), and microbiota alterations (86.1%). A progressive increase in Doxy-PEP use is anticipated, driven by patient demand, community influences, and international guidelines. Dermatologists of Italian STI centers demonstrate appropriate awareness of Doxy-PEP but maintain cautious attitudes toward efficacy and show a substantial concern about antibiotic resistance.
Facial and genital plaques are common manifestations of psoriasis, are challenging to treat, and significantly impact patients' quality of life (QoL). GULLIVER is a prospective, non-interventional study conducted in 2020-2023 in Italy, aimed at examining the effectiveness, safety and QoL impact of guselkumab through 52 weeks of treatment in patients with facial and/or genital psoriasis. The primary endpoint was the percentage of patients achieving a static Physician Global Assessment (sPGA) score of ≤1 and a minimum 2-grade improvement in sPGA score at Week 52. Of 351 enrolled patients, 88.6% remained on guselkumab treatment at Week 52. The proportions of patients achieving the sPGA targets in the facial and genital groups, respectively, were 83.3% and 76.5% at week 12, increasing to 93.8% and 97.9% at Week 52. Mean Dermatology Life Quality Index score improved from 12.0 ± 7.5 at baseline to 1.1 ± 2.0 at Week 52 for patients with facial psoriasis (p-value <0.001) and from 12.0 ± 6.9 to 1.6 ± 3.5 for those with genital psoriasis (p-value <0.001). Guselkumab was well-tolerated and no new safety signals were identified. This Italian real-world study demonstrated the high effectiveness and a good safety profile of guselkumab in treating facial and genital psoriasis.
Melanoma is recognized as the most aggressive type of skin cancer, characterized by its high mortality rates and significant therapeutic challenges. The primary aim of this research is to analyze cellular heterogeneity in SKCM through single-cell RNA sequencing (scRNA-seq) and construct a neddylation-related prognostic model. The scRNA-seq and bulk data of Skin Cutaneous Melanoma (SKCM) samples were obtained from Gene Expression Omnibus and Cancer Genome Atlas Program databases. The nonnegative matrix factorization clustering algorithm was employed to stratify malignant cells into different neddylation cell subtypes in SKCM. The scRNA-seq analysis classified 31,894 high-quality cells into eight major cell types, revealing significant cellular distribution patterns within the TME. We observed that neddylation activity was significantly elevated in SKCM tissues compared to normal counterparts. Based on the expression profile of prognostic NRGs, the malignant cells were stratified into four neddylation cell subtypes in SKCM. A neddylation-related prognostic signature (NRPS) was established based on marker genes of neddylation-C3 cell subtype. The low-risk group activated immune-related signaling pathways, while the high-risk group activated various cancer-related pathways. Notably, the low-risk group exhibited better overall survival, higher immune cell infiltration, and response rates to immunotherapy compared to the high-risk group. This investigation emphasizes the crucial function of NRGs in the prognosis of SKCM, while also underscoring the importance of understanding the TME and its cellular heterogeneity. The distinct cellular composition and functional attributes within the TME highlight the potential for immunotherapy responses that can be stratified by risk.
Although AD and HS are significantly different clinically, they share common systemic comorbidities and some immunological pathways. The aim of this multicentric Italian retrospective study is to assess therapeutic effects of upadacitinib on concomitant HS in AD patients. Multicentric, observational, real-life retrospective study on 195 patients with moderate to severe AD treated with upadacitinib. Specifically, a subgroup analysis of AD+HS patients was conducted. Demographic, clinical data, outcome measures (EASI, NRS itch, sleep and pain, DLQI POEM and ADCT) were collected at baseline (week 0) and at subsequent time points (week 4, week 16, week 32, and week 52). Additionally, IHS4 IHS4-55 and HiSCR were the tools used to evaluate the clinical course of HS in the AD+HS subgroup. A total of 195 AD patients were included, 7 (3,6%) patients also suffered of concomitant HS. In the AD+HS subgroup, mean IHS4 decreased from 6.9 ± 4.3 at baseline to 2.2 ± 1.8 at week 16 and 0.2 ± 0.5 at week 32. Reductions of mean baseline severity of HS tool (IHS4) score was detected as early as after only 4 weeks of treatment. Accordingly, HiSCR and HIS4-S5 were achieved by 4/7 patients at week 4, 5/6 at week 16, and 4/4 at week 32. In the AD+HS subgroup, improvements were observed for both AD and HS-specific outcomes. Our data, although preliminary, show that upadacitinib could be a valid therapeutic choice in the treatment of patients with AD and concomitant HS.
Acne vulgaris is a common dermatological condition among young adults. It can cause psychosocial consequences that go beyond its physical effects. This study aims to assess acne prevalence and its impact on quality of life, social appearance anxiety, and treatment practices among university students in northern Bangladesh. A cross-sectional survey was conducted among 1067 students to assess acne prevalence and severity (Global Acne Grading System, GAGS). Quality of life, social appearance anxiety, and psychological distress were measured using the Dermatology Life Quality Index (DLQI), Social Appearance Anxiety Scale (SAAS), and Hospital Anxiety and Depression Scale (HADS). Sociodemographic, lifestyle, and familial factors were also evaluated. Descriptive statistics, chi-square tests, and binary logistic regression were used to identify significant associations and predictors. Acne was reported by 47.6% of participants. Among those affected (n = 465), 47.96% had mild acne, 44.95% had moderate acne, 6.02% had severe acne, and 1.08% had very severe acne. Increasing acne severity was significantly associated with poorer quality of life (p < 0.001) and higher social appearance anxiety (p = 0.013). Logistic regression identified several independent predictors of acne, including gender (p = 0.008), residence (p ≤ 0.033), middle-income status (p = 0.040), belief that diet affects acne (p < 0.001), smoking (p = 0.023), alcohol consumption (p = 0.001), and family history of acne (p < 0.001). Higher DLQI scores were also significantly associated with acne (p = 0.002), whereas SAAS and HADS were not independently associated. Among affected individuals, 33.7% consulted a dermatologist, while others relied on self-medication (29.9%), home remedies (30.8%), or combined approaches (23.7%). Acne vulgaris is highly prevalent among young adults in northern Bangladesh and substantially impacts quality of life and social appearance. Its development involves a multifactorial interplay of genetic, lifestyle, and psychosocial factors, emphasizing the need for evidence-based management, lifestyle interventions, and psychosocial support in student health programs. Future research should examine causal pathways and guide comprehensive prevention and treatment strategies.
Patients with skin of color (SOC) face unique dermatologic challenges that are often underrepresented in research and in dermatological education, creating critical gaps in care. We aimed to identify and explore key gaps in research and clinical management for SOC across four domains: skin diseases, hair disorders, photoprotection, and aesthetic procedures. An international panel reviewed articles retrieved from PubMed using the search terms "skin of color" or "skin of colour" in titles and abstracts from September 2019 to September 2024. Inflammatory skin diseases, including acne, atopic dermatitis, psoriasis, and rosacea, are common in SOC subjects, necessitating tailored diagnostic and therapeutic approaches due to unique clinical presentations and specific challenges such as post-inflammatory hyperpigmentation and erythema detection. Pigmentary disorders such as melasma and acne-induced hyperpigmentation significantly impact quality of life in SOC, requiring cautious treatment to avoid exacerbation, while the unregulated use of skin bleaching agents containing high-potency corticosteroids can pose serious health risks. Skin cancer in SOC often presents at advanced stages with poorer outcomes due to lower awareness and unique clinical manifestations, resulting in delayed diagnosis. Hair disorders in SOC populations require tailored diagnostic and therapeutic approaches due to unique hair properties. Gaps in photoprotection education on SOC exacerbate pigmentary disorders and other dermatologic conditions, with limited research on effective sunscreens for this population. In aesthetic dermatology, misconceptions and knowledge gaps regarding the prevention of complications hinder access to safe and effective procedures for SOC subjects, compounded by inadequate diversity in clinical trials. Inclusive research, improved diagnostic accuracy, and customized procedures are needed to ensure equitable dermatologic care.
The clinical definition of moderate psoriasis is debated, affecting treatment eligibility and patient outcomes. A panel of Italian dermatologists aimed to propose practical criteria to define moderate psoriasis, based on a comprehensive literature review and clinical experience. The panel reviewed publications between 2016 and 2024 focusing on key severity scores, including the Psoriasis Area and Severity Index (PASI), Body Surface Area (BSA), Dermatology Life Quality Index (DLQI), and Physician's Global Assessment (PGA), along with special area involvement and patient-reported outcomes. Despite variability among studies, and the lack of universally accepted thresholds, the panel defined moderate psoriasis as a BSA of 5%-10%, DLQI of 5-10, a PGA score of 3, and involvement of at least two special areas (e.g. scalp, face, genitals, nails, hands, or feet). Distressing itch and psychosocial impact were also recognized as critical elements influencing perceived disease burden. A composite PGA-based approach, integrating objective measures with patient-centered criteria, is proposed for identifying patients with moderate psoriasis who may benefit from systemic therapy. This pragmatic approach may help bridge the gap between guidelines and real-world clinical practice, ensuring more accurate treatment allocation and reducing undertreatment of psoriasis.
Vitiligo is a chronic autoimmune depigmenting disorder. Ruxolitinib 1.5% cream is currently the only therapy specifically approved for its treatment. In addition, clinical guidelines recommend off label standard therapies, including topical corticosteroids (TCS), topical calcineurin inhibitors (TCI), phototherapy (narrowband UVB or excimer devices), and selected off-label systemic regimens. This review summarizes the scientific evidence on approved and guideline-recommended treatments for adult vitiligo, using a PRISMA-based approach. Only English-language articles published between 2000 and 2025 were included. Interventions comprised approved therapies and standard treatments recommended by guidelines. Outcomes evaluated were changes in Facial and Total Vitiligo Area Scoring Index (F-VASI/T-VASI), quality of life, and safety. Risk of bias was assessed using the Risk of Bias 2 (RoB 2) tool for randomized controlled trials (RCTs) and the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) for non-randomized studies. Ruxolitinib cream demonstrated superior F-VASI responses compared with vehicles in phase II-III RCTs. Evidence supports the efficacy of potent or very potent TCS, TCI, and NB-UVB or targeted 308-nm devices in localized disease. Systemic regimens show benefits in selected clinical scenarios, although supporting evidence remains heterogeneous. Treatment selection should be individualized based on disease activity, extent, anatomical site, and patient preferences.
Tonsillectomy improves symptoms in patients with palmoplantar pustulosis (PPP) and suppresses disease progression in patients with pustulotic arthro-osteitis (PAO), highlighting the important role of tonsils in the pathogenesis of PPP/PAO. To identify inflammatory pathways involved in the tonsil tissue of patients with PPP/PAO, and to clarify the characteristics of tonsillar microbiota. We assessed gene expression in tonsil tissue obtained from PPP/PAO or recurrent tonsillitis (RT)/sleep apnea syndrome (SAS) patients using microarray and quantitative reverse transcription polymerase chain reaction analysis. We also performed a comprehensive analysis of the tonsillar microbiota using next-generation sequencing. Potential associations between tonsillar gene expression and bacterial composition or disease activities were evaluated. Twenty-five tonsils from PPP/PAO patients and 15 tonsils from RT/SAS patients were included. The gene expression of inflammatory cytokines and molecules involved in the Th17, Th2, and Treg pathways was significantly higher in PPP/PAO tonsils than in RT/SAS tonsils. A significant positive correlation between Streptococcus spp. and the expression of Th17 and Th2 pathway genes was revealed both in PPP/PAO and RT/SAS, however, different correlation patterns were observed between these groups for the other genera. PAO disease activity showed a negative correlation with the expression of CCR4, FOXP3, and CXCR3 genes. PPP/PAO tonsils exhibit enhanced Th17, Th2, and Treg responses relative to RT/SAS, indicating a complex inflammatory condition. Streptococcus genus may be associated with inflammation, and interaction between microbiota and T cell immunity would be suggested in PPP/PAO tonsils. PAO disease activity inversely correlated with Treg response.
Nagashima-type palmoplantar keratosis (NPPK), the most common form of hereditary palmoplantar keratodermas in East Asian populations, is caused by biallelic loss-of-function mutations in SERPINB7 such as p.Arg266Ter (c.796 C>T). This mutation introduces a premature termination codon (PTC). Given the minimal efficacy of current drugs in improving NPPK skin phenotypes, we applied readthrough therapy to enable the production of functional proteins by allowing ribosomes to read through premature stop codons. To discover small molecule compounds with readthrough potency. Using high-throughput screening, we initially screened nearly 20,000 small molecule compounds. Using Western blot, we assessed the readthrough effectiveness of shortlisted compounds on the mutant SERPINB7 vector. We identified a promising compound and acquired structurally related compounds, comparing then their potency with that of gentamicin and ataluren. In addition, we evaluated the readthrough capability of the identified compounds on other 11 premature termination codons with different + 4 nucleotides. The identified hit compounds demonstrated superior readthrough efficacy than gentamicin and ataluren. Notably, our compounds were effective in enabling readthrough, particularly on UGAA and UAAG premature stop codons. Our research identified new compounds that effectively promote the readthrough of premature stop codons. In vitro, these compounds showed higher readthrough potency than drugs such as gentamicin or ataluren. These results suggest that these compounds could be promising therapeutic agents for genetic diseases caused by nonsense mutations.
Generalized pustular psoriasis (GPP) is a rare and potentially life-threatening autoinflammatory skin disease characterized by widespread pustules and systemic inflammation. Accurate disease severity assessment is essential for appropriate management. To evaluate GPP severity, several scoring systems have been developed, including the Generalized Pustular Psoriasis Physician Global Assessment (GPPGA), Generalized Pustular Psoriasis Area and Severity Index (GPPASI), and Investigator's Global Assessment (IGA). In Japan, the Japanese Dermatological Association (JDA) score is commonly used, incorporating systemic inflammatory parameters, such as fever, serum C-reactive protein (CRP) level, and serum albumin level with skin conditions. This study aimed to compare the JDA score with other severity assessment tools and examine their correlation with the length of hospitalization. We retrospectively analyzed 23 hospitalizations of 13 patients with GPP admitted to Nihon University Itabashi Hospital between 2014 and 2024. The JDA score showed a significant positive correlation with the length of hospitalization (rs = 0.482, p = 0.023), whereas the GPPGA, GPPASI, and IGA scores did not show any significant correlation. CRP levels, albumin levels, and the CRP/albumin ratio were significantly correlated with the length of hospitalization and GPPGA and GPPASI scores. These findings suggest that the JDA score, which integrates cutaneous symptoms and systemic inflammatory parameters, provides a more comprehensive and clinically relevant assessment of GPP severity than other scoring systems. Additionally, serum CRP and albumin levels should be considered in the evaluation of disease activity and prediction of clinical outcomes.
Hereditary angioedema (HAE) is a rare genetic disease characterized by sudden onset of edema involving various organs. Among the three subtypes of the disease, HAE types I and II are caused by heterozygous variants in SERPING1 gene encoding C1 inhibitor (C1INH). The pathogenicity of each variant, however, has not fully been revealed. To assess the mechanism how a SERPING1 gene-variant identified in a patient with HAE type I caused the disease. Genetic analysis was conducted for a Japanese patient with HAE type I. The consequences resulting from the SERPING1 gene-variant were analyzed at mRNA levels. Overexpression studies in cultured cells were performed to analyze behavior of the mutant C1INH proteins. Effect of a small interfering RNA specific to the mutant SERPING1-mRNA on expression of wild-type C1INH was also tested. We identified a recurrent heterozygous variant c.820 A>G (p.Ile274Val) in the patient's SERPING1 gene. While we did not find any abnormalities in C1INH with the p.Ile274Val-variant, we found that the variant c.820 A>G caused an aberrant splicing event leading to a frameshift and a premature termination codon. This truncated protein clearly showed a dominant-negative effect against the wild-type C1INH. Finally, we showed that knock-down of the mutant SERPING1-mRNA recovered expression of the wild-type C1INH. A unique pathogenic mechanism for the SERPING1 gene-variant c.820 A>G has been disclosed. Furthermore, our findings have raised the possibility that RNA interference could be a new therapeutic tool for the disease.
Psoriasis is a systemic inflammatory skin disease for which new topical treatments are needed. Psoriatic inflammation is associated with overexpression of eukaryotic translation initiation factors (eIFs), which regulate gene expression in processes such as proliferation, apoptosis, and differentiation. However, their role in psoriasis remains unclear. To investigate the contribution of eIF1A and eIF3B to psoriasis pathogenesis and evaluate the therapeutic potential of their inhibition via small interfering RNA (siRNA). We used two mouse models reflecting different mechanisms of psoriasis: (i) topical application of imiquimod (IMQ) and (ii) K5.TGFβ transgenic mice promoting keratinocyte proliferation. eIF1A and eIF3B were inhibited by either topical or systemic siRNA administration. A 3D human psoriasis model was also used for validation. Inhibition of eIF1A and eIF3B reduced inflammation in both mouse models and the 3D human model. Downregulation of these factors normalized keratinocyte proliferation, epidermal thickness, and cytokine expression (e.g., TNFα, IL-1β, IL-17, IL-22). Differentiation markers such as KRT16 and FLG were restored. These findings suggest that eIF1A and eIF3B play a key role in maintaining the psoriatic inflammatory phenotype. Our findings reveal a translational imbalance in psoriasis and identify eIF1A and eIF3B as crucial regulators of disease pathophysiology. Targeting these factors represents a promising new therapeutic strategy for psoriasis treatment.
Idiopathic photosensitive skin disorders, or idiopathic photodermatoses, are characterized by abnormal reactions to sunlight and ultraviolet (UV) radiation. They encompass conditions such as actinic prurigo, chronic actinic dermatitis, solar urticaria, photoaggravated psoriasis, polymorphic light eruption and photoaggravated eczema. Treatment options remain limited, but monoclonal antibodies (such as dupilumab, omalizumab, adalimumab, ustekinumab) and Janus kinase (JAK) inhibitors (such as tofacitinib, baricitinib, upadacitinib) have emerged as promising potential therapies. To evaluate the short- and long-term efficacy of these biologics and JAK inhibitors in managing these conditions, despite their lack of formal approval. A literature search was conducted using PubMed, Google Scholar and the Wiley Online Library. Inclusion criteria focused on studies published between 1960 and 2025 investigating monoclonal antibodies and JAK inhibitors for idiopathic photodermatoses, excluding other treatment modalities. Thirty-two studies involving 96 patients met the inclusion criteria. Most studies were case series or reports. Findings indicated significant reductions in disease activity and improvement in quality-of-life metrics (such as the Dermatology Life Quality Index) across various conditions. The lack of high-quality studies and the reliance on case reports limit generalizability. Variations in treatment regimens and outcome measures pose additional challenges. Monoclonal antibodies and JAK inhibitors demonstrate promise in reducing symptoms and improving quality of life in idiopathic photosensitive skin disorders. As these treatments are not formally indicated for these conditions, further research is warranted to confirm their efficacy and safety. This review highlights the need for clinical trials to enhance understanding and management of these challenging dermatological conditions.
Pressure ulcers are refractory skin ulcers that frequently develop at pressure sites in elderly individuals and those with reduced physical activity, and effective preventive strategies are urgently needed. These ulcers are primarily caused by cutaneous ischemia-reperfusion (I/R) injury, in which inflammation and oxidative stress play important roles. JAK inhibitors are widely used for inflammatory disorders and are also known to possess antioxidant effects. However, their therapeutic potential in cutaneous I/R injury remains unclear. This study aimed to investigate the role of JAK/STAT signaling and the efficacy of the selective JAK2/3 inhibitor AG490 in preventing ulcer formation in a murine cutaneous I/R model. In vivo, mice underwent four cycles of 3 h ischemia followed by 1 h reperfusion using magnetic skin compression. AG490 or vehicle was administered intraperitoneally before ischemia. In vitro, 10T1/2 cells were subjected to an oxygen-glucose deprivation/reoxygenation (OGD/R) model. Cutaneous I/R induced phosphorylation of JAK2 and STAT3, which was suppressed by AG490. On day 3, ulcer areas were significantly smaller in AG490-treated mice. AG490 also reduced inflammatory cell infiltration, apoptosis, and hypoxia, while enhancing Nrf2 activity in Keap1-dependent oxidative stress detector-luciferase (OKD-LUC) mice. In vitro, AG490 suppressed OGD/R-induced JAK/STAT activation, attenuated ROS production, prevented cell death, and enhanced the expression of HO-1. We demonstrated the protective effect of AG490 against I/R-induced skin damage through the attenuation of inflammation and oxidative stress, highlighting JAK inhibition as a promising approach for pressure ulcer prevention.