Apremilast is a potentially useful treatment for severe palmoplantar pustulosis with extra-palmoplantar symptoms.

Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disorder affecting the palms and soles. In rare cases, severe patients develop acute extra-palmoplantar lesions often accompanied by arthralgia. Such cases with extensive symptoms often necessitate systemic treatments with variable efficacy and potential side effects. Apremilast, known for its broad immune response modulation, presents promise as a therapeutic option for severe PPP with joint and extra-palmoplantar lesions. This case highlights apremilast as a potential systemic treatment for such cases with minimal side effects.

Best practices for multimodal clinical data management and integration: An atopic dermatitis research case.

BACKGROUND: In clinical research on multifactorial diseases such as atopic dermatitis, data-driven medical research has become more widely used as means to clarify diverse pathological conditions and to realize precision medicine. However, modern clinical data, characterized as large-scale, multimodal, and multi-center, causes difficulties in data integration and management, which limits productivity in clinical data science. METHODS: We designed a generic data management flow to collect, cleanse, and integrate data to handle different types of data generated at multiple institutions by 10 types of clinical studies. We developed MeDIA (Medical Data Integration Assistant), a software to browse the data in an integrated manner and extract subsets for analysis. RESULTS: MeDIA integrates and visualizes data and information on research participants obtained from multiple studies. It then provides a sophisticated interface that supports data management and helps data scientists retrieve the data sets they need. Furthermore, the system promotes the use of unified terms such as identifiers or sampling dates to reduce the cost of pre-processing by data analysts. We also propose best practices in clinical data management flow, which we learned from the development and implementation of MeDIA. CONCLUSIONS: The MeDIA system solves the problem of multimodal clinical data integration, from complex text data such as medical records to big data such as omics data from a large number of patients. The system and the proposed best practices can be applied not only to allergic diseases but also to other diseases to promote data-driven medical research.

Multifaceted analysis of cross-tissue transcriptomes reveals phenotype-endotype associations in atopic dermatitis.

Atopic dermatitis (AD) is a skin disease that is heterogeneous both in terms of clinical manifestations and molecular profiles. It is increasingly recognized that AD is a systemic rather than a local disease and should be assessed in the context of whole-body pathophysiology. Here we show, via integrated RNA-sequencing of skin tissue and peripheral blood mononuclear cell (PBMC) samples along with clinical data from 115 AD patients and 14 matched healthy controls, that specific clinical presentations associate with matching differential molecular signatures. We establish a regression model based on transcriptome modules identified in weighted gene co-expression network analysis to extract molecular features associated with detailed clinical phenotypes of AD. The two main, qualitatively differential skin manifestations of AD, erythema and papulation are distinguished by differential immunological signatures. We further apply the regression model to a longitudinal dataset of 30 AD patients for personalized monitoring, highlighting patient heterogeneity in disease trajectories. The longitudinal features of blood tests and PBMC transcriptome modules identify three patient clusters which are aligned with clinical severity and reflect treatment history. Our approach thus serves as a framework for effective clinical investigation to gain a holistic view on the pathophysiology of complex human diseases.

Comprehensive Genomic Characterization of Staphylococcus aureus Isolated from Atopic Dermatitis Patients in Japan: Correlations with Disease Severity, Eruption Type, and Anatomical Site.

Atopic dermatitis (AD) shows frequent recurrence. Staphylococcus aureus is the primary microbial component in AD and is associated with disease activity. However, traditional typing methods have failed to characterize virulent AD isolates at the clone level. We conducted a comprehensive genomic characterization of S. aureus strains isolated from the skin of AD patients and healthy donors, comparing the whole-genome sequences of the 261 isolates with anatomical and lesional (AD-A)/nonlesional (AD-NL)/healthy sites, eruption types, clinical scores, virulence, and antimicrobial resistance gene repertoires in Japan. Sequence type (ST) diversity was lost with worsening disease activity; ST188 was the most frequently detected ST in AD-A and had the strongest correlation with AD according to the culture rate and proportion with worsening disease activity. ST188 and ST20 isolates inhabited all skin conditions, with significantly higher proportions in AD skin than in healthy skin. ST8, ST15, and ST5 proportions were equivalent for all skin conditions; ST30 was detected only in healthy skin; and ST12 was detected only in AD skin. ST97 detected in AD-A and healthy skin was clearly branched into two subclades, designated ST97A and ST97H. A comparison of two genomes led to the discovery that only ST97A possessed the complete trp operon, enabling bacterial survival without exogenous tryptophan (Trp) on AD skin, where the Trp level was significantly reduced. Primary STs showing an AD skin inhabitation trend (ST188, ST97A, ST20, and ST12) were all trp operon positive. The predominant clones (ST188 and ST97) possessed almost no enterotoxin genes, no mecA gene, and few other antimicrobial resistance genes, different from the trend observed in Europe/North America. IMPORTANCE While Staphylococcus aureus is a member of the normal human skin flora, its strong association with the onset of atopic dermatitis (AD) has been suggested. However, previous studies failed to assign specific clones relevant to disease activities. Enterotoxins produced by S. aureus have been suggested to aggravate and exacerbate the inflammation of AD skin, but their role remains ambiguous. We conducted a nuanced comprehensive characterization of isolates from AD patients and healthy donors, comparing the whole-genome sequences of the isolates with anatomical and lesional/nonlesional/healthy sites, eruption types, clinical scores, virulence, and antimicrobial resistance gene repertoires in Japan. We demonstrate that specific clones are associated with disease severity and clinical manifestations, and the dominant clones are devoid of enterotoxin genes and antimicrobial resistance genes. These findings undermine the established notion of the pathophysiological function of S. aureus associated with AD and introduce a new concept of S. aureus colonization in AD.

Desmoglein-Specific B-Cell-Targeted Single-Cell Analysis Revealing Unique Gene Regulation in Patients with Pemphigus.

Autoreactive B cells are assumed to play a critical role in pemphigus; however, the characteristics of these cells are not yet fully understood. In this study, 23 pemphigus vulgaris or pemphigus foliaceus samples were used to isolate circulating desmoglein (DSG)-specific B cells. Transcriptome analysis of the samples was performed at the single-cell level to detect genes involved in disease activity. DSG1- or DSG3-specific B cells from three patients' differentially expressed genes related to T cell costimulation (CD137L) as well as B-cell differentiation (CD9, BATF, TIMP1) and inflammation (S100A8, S100A9, CCR3), compared with nonspecific B cells from the same patients. When the DSG1-specific B cells before and after treatment transcriptomes of the patient with pemphigus foliaceus were compared, there were changes in several B-cell activation pathways not detected in non-DSG1-specific B cells. This study clarifies the transcriptomic profile of autoreactive B cells in patients with pemphigus and documents the gene expression related to disease activity. Our approach can be applied to other autoimmune diseases and has the potential for future detection of disease-specific autoimmune cells.

Stratification of atopic dermatitis patients by patterns of response to proactive therapy with topical tacrolimus: low serum IgE levels and inadequately controlled disease activity at the start of treatment predict its failure.

PURPOSE: Topical calcineurin inhibitors (TCIs) are an important anti-inflammatory drug for treating atopic dermatitis (AD). However, those treatment responses are variable. In this study, we stratified AD patients by patterns of response to remission maintenance therapy (proactive therapy) with topical tacrolimus, a typical TCI. Thereafter, we explored patient features that predict the success or failure of proactive therapy using TCI (TCI proactive therapy). METHODS: A single-arm open-label clinical study aimed to evaluate the efficacy of TCI proactive therapy was conducted in 31 patients with AD. Patients were treated with TCS to induce remission (remission-induction period) followed by daily TCI ointment (0.1% tacrolimus) application for 4 weeks (maintenance therapy period), and twice-weekly application for 12 weeks (proactive therapy period). Based on its results, treatment outcomes were correlated with the patients' clinical and laboratory findings. RESULTS: Of the 31 patients enrolled in the study, 21 successfully completed maintenance therapy (TCI responders). Among them, 13 completed (proactive-completed group) and 8 failed proactive therapy (proactive-dropout group). At the beginning of maintenance therapy, the serum IgE level was significantly higher in the TCI responders than in those who failed maintenance therapy (p = 0.049). At the beginning of proactive therapy, the mean-SCORing Atopic Dermatitis (SCORAD) score was significantly different between the proactive-completed (11.7 ± 4.6) and proactive-dropout (16.6 ± 4.2) groups (p = 0.025). In proactive-dropout group patients, worsened disease activity correlated well with the elevation of serum lactate dehydrogenase (LDH) and Thymus and activation-regulated chemokine (TARC) levels and peripheral eosinophil count. CONCLUSION: AD patients were stratified into three different response patterns to TCI proactive therapy. Patients with less involvement of IgE in the pathogenesis and inadequate remission induction by TCS may not be expected to respond well to TCI proactive therapy.Key messagesAD patients can be stratified into three types according to their pattern of responsiveness to TCI proactive therapy.The efficacy of TCI proactive therapy is lower in AD patients with lower serum IgE levels.TCI proactive therapy should be done after the achievement of adequate remission induction by TCS.