Exploration of circulating metabolic signature of erythrodermic psoriasis based on LC-MS metabolomics.

Erythrodermic psoriasis (EP) is a rare and life-threatening disease, the pathogenesis of which remains to be largely unknown. Metabolomics analysis can provide global information on disease pathophysiology, candidate biomarkers, and potential intervention strategies. To gain a better understanding of the mechanisms of EP and explore the serum metabolic signature of EP, we conducted an untargeted metabolomics analysis from 20 EP patients and 20 healthy controls. Furthermore, targeted metabolomics for focused metabolites were identified in the serum samples of 30 EP patients and 30 psoriasis vulgaris (PsV) patients. In the untargeted analysis, a total of 2992 molecular features were extracted from each sample, and the peak intensity of each feature was obtained. Principal component analysis (PCA), orthogonal partial least squares-discriminant analysis (OPLS-DA) revealed significant difference between groups. After screening, 98 metabolites were found to be significantly dysregulated in EP, including 67 down-regulated and 31 up-regulated. EP patients had lower levels of L-tryptophan, L-isoleucine, retinol, lysophosphatidylcholine (LPC), and higher levels of betaine and uric acid. KEGG analysis showed differential metabolites were enriched in amino acid metabolism and glycerophospholipid metabolism. The targeted metabolomics showed lower L-tryptophan in EP than PsV with significant difference and L-tryptophan levels were negatively correlated with the PASI scores. The serum metabolic signature of EP was discovered. Amino acid and glycerophospholipid metabolism were dysregulated in EP. The metabolite differences provide clues for pathogenesis of EP and they may provide insights for therapeutic interventions.

Biologics in pediatric psoriasis.

Psoriasis is a chronic inflammatory skin disorder with a chronic relapsing course. Biologics have revolutionized the treatment of adult psoriasis with higher efficacy and favorable safety profile. Recently, more studies have focused on the use of biologics in pediatric psoriasis, and several biologics have been approved for use therein. This review is divided into two sections: the first part focuses on real-world studies on the use of biologics in pediatric psoriasis and the second part summarizes the findings of other clinical trials related to biologics in pediatric psoriasis. Case reports have been excluded from this review. Several biologics were used for treating pediatric psoriasis and the efficacy is encouraging. According to the studies included in this review, anti-IL-12/23 and anti-IL-17A for treating pediatric psoriasis might have a better efficacy than anti-TNF-α, but more data are needed.

Expression of Thymic Stromal Lymphopoietin in Immune-Related Dermatoses.

Thymic stromal lymphopoietin (TSLP), long known to be involved in Th2 response, is also implicated in multiple inflammatory dermatoses and cancers. The purpose of this study was to improve our understanding of the expression of TSLP in the skin of those dermatoses. Lesional specimens of representative immune-related dermatoses, including lichen planus (LP), discoid lupus erythematosus (DLE), eczema, bullous pemphigoid (BP), psoriasis vulgaris (PsV), sarcoidosis, and mycosis fungoides (MF), were retrospectively collected and analyzed by immunohistochemistry. Morphologically, TSLP was extensively expressed in the epidermis of each dermatosis, but the expression was weak in specimens of DLE. In a semiquantitative analysis, TSLP was significantly expressed in the epidermis in LP, BP, eczema, PsV, sarcoidosis, and MF. TSLP expression was higher in the stratum spinosum in LP, eczema, BP, PsV, and MF and higher in the stratum basale in sarcoidosis and PsV. Moreover, we found positive TSLP staining in the dermal infiltrating inflammatory cells of BP, PsV, and sarcoidosis. Our observation of TSLP in different inflammatory dermatoses might provide a novel understanding of TSLP in the mechanism of diseases with distinctly different immune response patterns and suggest a potential novel therapeutic target of those diseases.

A comparative study of melanocytic nevi classification with dermoscopy and high-frequency ultrasound.

BACKGROUND: Melanocytic nevi (MN) can be classified into three subtypes according to the depth of the nests of nevus cells which is important for management. High-frequency ultrasound (HF-US) can clearly reveal the lesion size, contour, depth, and internal structures. However, the HF-US studies of MN according to subtypes are limited. We aimed to describe the HF-US features of MN and explore its value in accurate classification. MATERIALS AND METHODS: This retrospective study was conducted from January 2018 to November 2019. Eighty-five patients with MN were included and examined by 50 and 20 MHz HF-US. The HF-US features were recorded including morphological flatness, depth, shape, boundary, internal echogenicity, hyperechoic spots, lateral acoustic shadow, posterior echoic patterns, mushroom signs, and straw-hat signs. Each image was evaluated by two physicians independently, and the consistency was tested. RESULTS: Eleven lesions could not be detected by HF-US. The rest 74 lesions underwent ultrasonic analysis. MN appeared as strip-shaped or oval, hypoechoic areas localized in the epidermis and dermis under ultrasonography. A strong consistency between HF-US and dermoscopy of determining the lesion depth was achieved (κ = 0.935, p < 0.001). The hyperechoic spots were found in 57.6% intradermal nevi. The mushroom signs were seen in 34.8% intradermal nevi, and the straw-hat signs were seen in all the compound nevi. CONCLUSION: MN can be correctly classified using HF-US, and it had a strong correlation with dermoscopic and clinical classification. HF-US could further reveal the internal morphological features of MN, which may support more precise classification and management.

Neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, and other hematological parameters in psoriasis patients.

BACKGROUND: Psoriasis is a chronic immune-mediated skin disorder. Systemic inflammation plays an important role in the pathogenesis of psoriasis. METHODS: A total of 477 patients with psoriasis vulgaris (PsV, n = 347), generalized pustular psoriasis (GPP, n = 37), erythrodermic psoriasis (PsE, n = 45), arthritic psoriasis (PsA, n = 25) and mixed psoriasis (n = 23), and 954 healthy control subjects were included in the study. Demographic, clinical, and laboratory information were collected and compared between subgroups. RESULTS: Compared with the healthy control group, patients with psoriasis had higher total white blood cell (WBC), neutrophil, platelet counts, neutrophil to lymphocyte ratio (NLR), and platelet to lymphocyte ratio (PLR), but lower hemoglobin (Hb) levels, lymphocyte and red blood cell (RBC) counts. NLR values in the PsV group were significantly lower than those in the GPP, PsE, and PsA groups, with GPP group being the highest. PLR values in the PsV group were significantly lower than those in the GPP, PsE, and PsA groups. There was no significant correlation between the psoriasis area severity index (PASI) score and either the NLR or PLR in the PsV group. CONCLUSIONS: Elevated NLR and PLR were associated with psoriasis and differed between subtypes, suggesting that they could be used as markers of systemic inflammation in psoriasis patients.

Deep learning-based, computer-aided classifier developed with dermoscopic images shows comparable performance to 164 dermatologists in cutaneous disease diagnosis in the Chinese population.

BACKGROUND: Diagnoses of Skin diseases are frequently delayed in China due to lack of dermatologists. A deep learning-based diagnosis supporting system can facilitate pre-screening patients to prioritize dermatologists' efforts. We aimed to evaluate the classification sensitivity and specificity of deep learning models to classify skin tumors and psoriasis for Chinese population with a modest number of dermoscopic images. METHODS: We developed a convolutional neural network (CNN) based on two datasets from a consecutive series of patients who underwent the dermoscopy in the clinic of the Department of Dermatology, Peking Union Medical College Hospital, between 2016 and 2018, prospectively. In order to evaluate the feasibility of the algorithm, we used two datasets. Dataset I consisted of 7192 dermoscopic images for a multi-class model to differentiate three most common skin tumors and other diseases. Dataset II consisted of 3115 dermoscopic images for a two-class model to classify psoriasis from other inflammatory diseases. We compared the performance of CNN with 164 dermatologists in a reader study with 130 dermoscopic images. The experts' consensus was used as the reference standard except for the cases of basal cell carcinoma (BCC), which were all confirmed by histopathology. RESULTS: The accuracies of multi-class and two-class models were 81.49% ±â€Š0.88% and 77.02% ±â€Š1.81%, respectively. In the reader study, for the multi-class tasks, the diagnosis sensitivity and specificity of 164 dermatologists were 0.770 and 0.962 for BCC, 0.807 and 0.897 for melanocytic nevus, 0.624 and 0.976 for seborrheic keratosis, 0.939 and 0.875 for the "others" group, respectively; the diagnosis sensitivity and specificity of multi-class CNN were 0.800 and 1.000 for BCC, 0.800 and 0.840 for melanocytic nevus, 0.850 and 0.940 for seborrheic keratosis, 0.750 and 0.940 for the "others" group, respectively. For the two-class tasks, the sensitivity and specificity of dermatologists and CNN for classifying psoriasis were 0.872 and 0.838, 1.000 and 0.605, respectively. Both the dermatologists and CNN achieved at least moderate consistency with the reference standard, and there was no significant difference in Kappa coefficients between them (P > 0.05). CONCLUSIONS: The performance of CNN developed with relatively modest number of dermoscopic images of skin tumors and psoriasis for Chinese population is comparable with 164 dermatologists. These two models could be used for screening in patients suspected with skin tumors and psoriasis respectively in primary care hospital.

Biologics in the treatment of pustular psoriasis.

INTRODUCTION: Pustular psoriasis is a group of skin diseases characterized by neutrophil infiltration in the epidermis and formation of sterile pustules. Conventional treatments, such as retinoids and immunosuppressive drugs, have improved the clinical manifestations; however, many patients suffer from drug-related toxicity or are resistant to therapy. AREAS COVERED: In this review, the authors focus on the efficacy and safety of these biologics, including anti-IL-1ß (gevokizumab and canakinumab), anti-IL-1 R (anakinra), anti-IL-36 R (BI 655130), anti-tumor necrosis factor-α (etanercept, infliximab, and adalimumab), anti-IL-12/23 (ustekinumab), anti-IL-17A (secukinumab and ixekizumab), anti-IL-17RA (brodalumab), anti-IL-2 R (basiliximab), anti-IL-6 R (tocilizumab), and anti-IL-23 (risankizumab and guselkumab), for treating pustular psoriasis. EXPERT OPINION: Patients with pustular psoriasis treated with biologics demonstrated positive responses. Anti-TNF-α is the most available biologics for the treatment of pustular psoriasis, and anti-IL-12/23 and anti-IL-17A might be considered as the first- or second-line therapy for moderate-to-severe and refractory pustular psoriasis. Anti-IL-17A can be used in the pustular psoriasis patients who failed to respond to anti-TNF agents and anti-IL-12/23. Therapeutic efficacy of biologics in pustular psoriasis might have no association with IL-36 RN mutation status.

RNA N6-Methyladenosine Modifications and the Immune Response.

N6-methyladenosine (m6A) is the most important modification of messenger RNAs (mRNAs) and long noncoding RNAs (lncRNAs) in higher eukaryotes. Modulation of m6A modifications relies on methyltransferases and demethylases. The discovery of binding proteins confirms that the m6A modification has a wide range of biological effects and significance at the molecular, cellular, and physiological levels. In recent years, techniques for investigating m6A modifications of RNA have developed rapidly. This article reviews the biological significance of RNA m6A modifications in the innate immune response, adaptive immune response, and viral infection.

Retinol and vitamin A metabolites accumulate through RBP4 and STRA6 changes in a psoriasis murine model.

BACKGROUND: Psoriasis is a common chronic inflammatory skin disease that features the abnormal proliferation of keratinocytes. This proliferation could partly result from disturbances in vitamin A metabolism. Changes in psoriasis patients of the levels of retinol-binding protein 4 (RBP4), a carrier of retinol (vitamin A); transmembrane protein stimulated by retinoic acid 6 (STRA6); and other retinol metabolic molecules have not yet been fully established. Therefore, we investigated vitamin A-related proteins in mice with imiquimod (IMQ)-induced psoriasis. METHODS: Thirty mice were divided into four study groups: two groups underwent IMQ application for 3 or 6 days (groups A and B, respectively), and two groups underwent Vaseline application for 3 or 6 days (groups C and D, respectively). Blood and skin samples from both lesional and non-lesional areas of the mice were analyzed using enzyme-linked immunosorbent assays, hematoxylin and eosin staining, immunochemistry, real-time reverse transcription polymerase chain reaction, and RNA sequencing. RESULTS: IMQ-treated mice developed erythema, scales, and skin thickening. Compared with the control groups, IMQ-treated groups had the following changes: 1) interleukin (IL)-17A, IL-23, and tumor necrosis factor (TNF)-α levels were raised significantly in both serum and lesional skin (all p < 0.001); 2) retinol levels in lesional skin increased slightly (p = 0.364), but no change was evident in serum retinol levels; 3) STRA6 was upregulated in both lesional skin (p = 0.021) and serum (p = 0.034); 4) RBP4 levels were elevated in serum (p = 0.042), but exhibited only an increasing trend (p = 0.273) in lesional skin; and 5) proteins and enzymes that mediate retinoic acid formation and transformation were upregulated in lesional skin. CONCLUSIONS: As the demand for vitamin A in psoriatic mice increased, retinol underwent relocation from the circulation to target tissues. RBP4, STRA6, and the transformation from retinol to retinoic acid were upregulated, which may be part of the mechanism of psoriasis skin lesion formation. We propose that a positive feedback mechanism was formed that maintained the severity of psoriasis.

Etanercept biosimilar (recombinant human tumor necrosis factor-α receptor II: IgG Fc fusion protein) and methotrexate combination therapy in Chinese patients with moderate-to-severe plaque psoriasis: a multicentre, randomized, double-blind, placebo-controlled trial.

Etanercept biosimilar recombinant human tumour necrosis factor-α receptor II: IgG Fc fusion protein (rhTNFR-Fc, trade name Yisaipu) has shown good efficacy in the treatment of moderate-to-severe plaque psoriasis. To compare the efficacy and safety of rhTNFR-Fc plus methotrexate (MTX) and rhTNFR-Fc plus placebo in Chinese patients with moderate-to-severe plaque psoriasis. In this multicentre, randomized, placebo-controlled trial, patients with moderate-to-severe plaque psoriasis were enrolled and randomly assigned in a 1:1 ratio to receive rhTNFR-Fc plus MTX or rhTNFR-Fc plus placebo. The primary endpoint was the proportion of patients achieving Psoriasis Area and Severity Index improvement of at least 75% (PASI 75) from baseline at week 24. Adverse events (AEs) were recorded to evaluate safety. Efficacy analysis was performed using the intent-to-treat principle. A total of 466 patients were enrolled and randomly received rhTNFR-Fc plus MTX (combination group, n = 233) or rhTNFR-Fc plus placebo (monotherapy group, n = 233). PASI 75 at week 24 was significantly higher in the combination group than in the monotherapy group (81.86% vs. 65.50%, p < 0.001). Similar results were observed in other PASI improvement scores at week 12 [PASI 75, 62.39% vs. 44.54% (p < 0.001); PASI 50, 87.17% vs. 75.55% (p = 0.001); and PASI 90, 34.07% vs. 18.78% (p < 0.001)] and week 24 [PASI 50, 92.48% vs. 85.59% (p = 0.019); and PASI 90, 64.16% vs. 42.36% (p < 0.001)]. Significantly more patients had a static Physicians' Global Assessment of clear or almost clear in the combination group than in the monotherapy group at week 12 (26.46% vs. 12.50%, p < 0.001) and week 24 (62.38% vs. 40.83%, p < 0.001). The most common AEs in the two groups were upper respiratory tract infection and abnormal liver function. The combination therapy of rhTNFR-Fc plus MTX was an effective therapy for moderate-to-severe plaque psoriasis with an acceptable safety and tolerability profile, indicating that it was feasible and well tolerated for patients.

IL-36ß Promotes Inflammatory Activity and Inhibits Differentiation of Keratinocytes In Vitro.

Objective Psoriasis is an immune-mediated inflammatory disease. Despite advances in the study of its pathogenesis, the exact development mechanism of psoriasis remains to be fully elucidated. Hyperproliferative epidermis plays a crucial role in psoriasis. This study aimed to investigate the effects of interleukin-36ß (IL-36ß) on keratinocyte dysfunction in vitro. Methods Human keratinocyte cell lines, HaCaT cells, were treated with 0 (control), 50 or 100 ng/ml IL-36ß respectively for 24 h. Cell viability was determined with a cell counting kit-8 assay. Flow cytometry was used to assess the effects of IL-36ß on apoptosis and cell cycle distribution. Expressions of the differentiation markers, such as keratin 10 and involucrin, were evaluated by quantitative real-time polymerase chain reaction (RT-qPCR). Expressions of the inflammatory cytokines, IL-1ß and IL-6 were tested by ELISA. Results CCK8 assay showed the survival rate had no significant difference between the control and treated group (P > 0.05). Flow cytometry analysis showed cell cycle arrest at S phase in the IL-36ß-treated groups compared with the control group (P < 0.05). RT-qPCR verified the decreased mRNA expressions of keratin 10 and involucrin in the IL-36ß-treated groups compared with the negative control (P < 0.01). ELISA showed 100 ng/ml IL-36ß enhanced levels of IL-1ß and IL-6 in culture supernatants of HaCaT cells compared with the negative control (P < 0.05). Conclusion Taken together, these findings suggest that IL-36ß could induce cell cycle arrest at S phase, inhibit keratin 10 and involucrin expressions and promote inflammatory activity in HaCaT cell lines.

Double-edge Role of B Cells in Tumor Immunity: Potential Molecular Mechanism.

B cells are a heterogeneous population, which have distinct functions of antigen presentation, activating T cells, and secreting antibodies, cytokines as well as protease. It is supposed that the balance among these B cells subpopulation (resting B cells, activated B cells, Bregs, and other differentiated B cells) will determine the ultimate role of B cells in tumor immunity. There has been increasing evidence supporting opposite roles of B cells in tumor immunity, though there are no general acceptable phenotypes for them. Recent years, a new designated subset of B cells identified as Bregs has emerged from immunosuppressive and/or regulatory functions in tumor immune responses. Therefore, transferring activated B cells would be possible to become a promising strategy against tumor via conquering the immunosuppressive status of B cells in future. Understanding the potential mechanism of double-edge role of B cells will help researchers utilize activated B cells to improve their anti-tumor response. Moreover, the molecular pathways related to B cell differentiation are involved in its tumor-promoting effect, such as NF-κB, STAT3, BTK. So, we review the molecular and signaling pathway mechanisms of B cells involved in both tumor-promoting and tumor-suppressive immunity, in order to help researchers optimize B cells to fight cancer better.

High-frequency ultrasound features of basal cell carcinoma and its association with histological recurrence risk.

BACKGROUND: Due to advances in high-frequency ultrasound technology, it is easier to detect fine structures of skin lesions. The aim of this study was to examine the ultrasonographic features and use recurrence risk stratification to assess the diagnostic performance of pre-operative ultrasound examination of basal cell carcinoma (BCC). METHODS: This was a retrospective study. Forty-six BCC lesions underwent pre-operative ultrasound examination using 50- and 20-MHz probes. Ultrasonographic shape, margin, internal echoes, hyper-echoic spots, posterior echoes, and depth of the lesion were evaluated and correlated with the risk of recurrence based on histological features. RESULTS: Forty-two patients had 46 skin lesions in total. The high-risk (n = 6) and low-risk (n = 40) groups exhibited considerable overlap in the ultrasonographic manifestations and no significant difference in margin (χ = 3.231, P = 0.072), internal echo (χ = 1.592, P = 0.207), or posterior echo (P = 0.169). However, high-risk BCCs tended to be irregular in shape than low-risk lesions (χ = 4.313, P = 0.038). Both types presented hyper-echoic spots (χ = 1.850, P = 0.174). Additionally, 78% of low-risk lesions were confined to the dermis (31/40), and 100% of high-risk lesions infiltrated into the sub-cutaneous tissue, resulting in a significant difference between the two groups (χ = 10.951, P = 0.001). Ultrasound detected sub-clinical lesions in five patients. CONCLUSIONS: High-frequency ultrasound can provide important information for pre-operative evaluation of risk in BCC foci and reveal hidden lesions. The technique may play a crucial role in guiding therapeutic options for BCC.

Long-Term Follow-Up of Longevity and Diffusion Pattern of Hyaluronic Acid in Nasolabial Fold Correction through High-Frequency Ultrasound.

BACKGROUND: Injectable hyaluronic acid fillers have been widely applied in the clinical treatment of facial wrinkles. However, further information and clinical evidence concerning dermal changes and hyaluronic acid filler longevity after injection and diffusion pattern are limited. METHODS: The authors evaluated the longevity and diffusion pattern of two hyaluronic acid fillers generated by different cross-linking technologies used in the treatment of nasolabial folds using high-frequency ultrasound. Forty-one subjects were treated with Restylane 2 and the remaining 41 were treated with Dermalax DEEP. Wrinkle severity rating scale score and high-frequency ultrasound evaluation of nasolabial folds were performed before and after the injection of hyaluronic acid filler. The ultrasound images were acquired and analyzed to determine dermal thickness and the shape and distribution of hyaluronic acid filler. RESULTS: At 2 and 24 weeks from baseline, increased dermal thickness induced by hyaluronic acid filler treatment was not significantly different between groups. At 48 weeks after injection, increased dermal thicknesses of the Restylane 2 group (0.14 ± 0.12 mm) were much lower than those of the Dermalax DEEP group (0.20 ± 0.13 mm). Ultrasound examination revealed that hyaluronic acid materials form well-demarcated and hypoechogenic areas. Restylane 2 tended to form a more diffuse pattern, with multiple smaller bubbles, whereas Dermalax DEEP developed into a more localized configuration, with larger clumps. CONCLUSIONS: This study is the first long-term assessment of nasolabial fold correction that reveals the performance of different hyaluronic acid materials in vivo and validates high-frequency ultrasound as a simple and rapid modality. Hyaluronic acid fillers generated by different cross-linking technologies display differential diffusion patterns in skin tissues. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.