The skin is our outer permeability and immune defense barrier against myriad external assaults. Aryl hydrocarbon receptor (AhR) senses environmental factors and regulates barrier robustness and immune homeostasis. AhR agonists have been approved by the FDA for psoriasis treatment and are in clinical trials for the treatment of atopic dermatitis (AD), but the underlying mechanism of action remains poorly defined. Here, we report that OVOL1/Ovol1 is a conserved and direct transcriptional target of AhR in epidermal keratinocytes. We show that OVOL1/Ovol1 influences AhR-mediated regulation of keratinocyte gene expression and that OVOL1/Ovol1 ablation in keratinocytes impairs the barrier-promoting function of AhR, exacerbating AD-like inflammation. Mechanistically, we have identified Ovol1’s direct downstream targets genome-wide and provided in vivo evidence supporting the role of Id1 as a functional target in barrier maintenance, disease suppression, and neutrophil accumulation. Furthermore, our findings reveal that an IL-1/dermal γδT cell axis exacerbates type 2 and 3 immune responses downstream of barrier perturbation in Ovol1-deficient AD skin. Finally, we present data suggesting the clinical relevance of OVOL1 and ID1 functions in human AD skin. Our study highlights a keratinocyte-intrinsic AhR-Ovol1-Id1 regulatory axis that promotes both epidermal and immune homeostasis in the context of skin inflammation, identifying new therapeutic targets.

ABSTRACT Skin is our outer permeability and immune defense barrier against myriad external assaults. Aryl hydrocarbon receptor (AhR) senses environmental factors and regulates barrier robustness and immune homeostasis. AhR agonist is in clinical trial for atopic dermatitis (AD) treatment, but the underlying mechanism of action remains ill-defined. Here we report OVOL1/Ovol1 as a conserved and direct transcriptional target of AhR in epidermal keratinocytes. We show that OVOL1/Ovol1 impacts AhR regulation of keratinocyte gene expression, and Ovol1 deletion in keratinocytes hampers AhR’s barrier promotion function and worsens AD-like inflammation. Mechanistically, we identify Ovol1’s direct downstream targets genome-wide, and provide in vivo evidence for Id1’s critical role in barrier maintenance and disease suppression. Furthermore, our findings reveal an IL-1/dermal γδT cell axis exacerbating both type 2 and type 3 immune responses downstream of barrier perturbation in Ovol1 -deficient AD skin. Finally, we present data suggesting the clinical relevance of OVOL1 and ID1 function in human AD. Our study highlights a keratinocyte-intrinsic AhR-Ovol1-Id1 regulatory axis that promotes both epidermal and immune homeostasis against AD-like inflammation, implicating new therapeutic targets for AD.

Background: In recent years, biologics targeting key cytokines and Janus kinase (JAK) inhibitors have demonstrated favorable efficacy and safety outcomes for atopic dermatitis (AD) therapy. To evaluate the short-term efficacy and safety of AD therapy involving biologics, JAK inhibitors, and their combination with topical corticosteroids (TCS) for patients with AD, we conducted this systematic review and meta-analysis. Using eligible randomized clinical trials (RCTs) of 12 or 16 weeks of treatment with systemic medications and 4 weeks of topical treatment for AD. Methods: PubMed, Web of Science, ScienceDirect, and the Cochrane Library were searched from inception up to October 25, 2023. English-language randomized clinical trials (RCTs) of 12 or 16 weeks of treatment with systemic medications and 4 weeks of topical treatment for AD were included. Titles, abstracts, and articles were screened in duplicate. Of 7261 citations, 37 studies were included. The data were analyzed using Review Manager 5.4 and the outcomes were measured by the Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), the pruritus Numerical Rating Scale (NRS), as well as instances of adverse events (AE), and serious AE (SAE), which were presented as risk ratio (RR) with a 95 % confidence interval (CI). The efficacy of the biological therapies was analyzed with the percentage of patients who have achieved EASI 75, EASI 90, IGA 0/1 and pruritus NRS4, while the safety of treatments was evaluated in terms of the number of patients who had ≥1 AE and who had at least one SAE. Results: A total of 37 studies with 43 cohorts that examined 9 medications and placebo and involved 18172 participants were included. Compared with the placebo, all biologics and JAK inhibitors were associated with a higher response rate in efficacy outcomes, while systematic administration was presented by dupilumab 200 mg subcutaneously every 2 weeks with superior improvement in EASI 90 (RR 9.50, 95 % CI 2.31–39.03) and IGA0/1 (RR 17.00, 95 % CI 2.33–123.78), upadacitinib 30 mg once daily in EASI 75 (RR 5.14, 95 % CI 4.20–6.31) and Pruritus NRS4 (RR 5.73, 95 % CI 4.44–7.39), and external use was presented by ruxolitinib 1.5 % twice daily orally in EASI 75 (RR 4.14, 95 % CI 3.06–5.61) and Pruritus NRS4 (RR 4.08, 95 % CI 2.86–5.81), and most of doses led to a better safety profile. Most doses of baricitinib, dupilumab, tralokinumab, and upadacitinib in combination with TCS demonstrated good efficacy as compared with the control groups (placebo + TCS). However, patients receiving baricitinib at a dosage of 2 mg daily (RR 1.23, 95 % CI 1.02–1.49) and 4 mg daily (RR 1.39, 95 % CI 1.22–1.58) in combination with TCS, exhibited a higher incidence of one or more SAE as compared with those taking placebo + TCS. Conclusion: Our research has revealed that ruxolitinib and dupilumab are effective and safe treatments for mild to moderate AD and moderate to severe AD, respectively. Additionally, the combination of dupilumab and TCS demonstrates greater efficacy and safety compared to baricitinib, tralokinumab, and upadacitinib with TCS as a background treatment for moderate to severe AD. We suggest that the use of topical JAK inhibitors could be a potential alternative to TCS when used in combination with systemic medications, as a novel approach to treat AD. Insufficient different data sources caused by partial interventions were only mentioned in a few articles and low event rates in safety analyses may lead to the results being biased. Further studies directly comparing existing and novel treatments are needed and will be included in forthcoming updates of this review. Our findings could form a useful foundation for developing a new generation of treatment guidelines for AD.

Background: Psoriasis is a common immune-mediated skin disease that involves T-cell-mediated immunity. Invariant natural killer T (iNKT) cells are a unique lymphocyte subpopulation that share properties and express surface markers of both NK cells and T cells. Previous reports indicate that iNKT cells regulate the development of various inflammatory diseases. IL-17 is a key cytokine in the pathogenesis of psoriasis and a key therapeutic target. Secukinumab is a fully human IgG1κ antibody that targets IL-17A, thereby antagonizing the biological effects of IL-17. Objective: To explore the expression of iNKT cells in psoriasis patients and the effect of secukinumab on them. Methods: We examined the frequencies of iNKT cells, Tregs, naïve and memory CD4+and CD8+T cells in the PBMCs as well as their cytokine production in a cohort of 40 patients with moderate-to-severe plaque psoriasis and 40 gender- and age-matched healthy controls. We further collected peripheral blood of another 15 moderate-to-severe plaque psoriasis patients who were treated with secukinumab and evaluated the proportion of iNKT cells in the PBMCs at baseline and week 12. Results: The frequencies of conventional CD4+ T cells, CD8+ T cells, and Tregs in the PBMCs were comparable between psoriasis patients and healthy controls, but the frequencies of Th17 cells, Tc1 cells and Tc17 cells were increased in psoriasis patients. The frequency of peripheral iNKT cells and CD69+iNKT cells was significantly decreased in psoriasis patients. Both iNKT2 cells and iNKT17 cells were increased in psoriasis patients, but the ratio of iNKT2 cells vs iNKT17 cells was significantly reduced in psoriasis patients. After receiving secukinumab, the proportion of iNKT cells in the PBMCs of patients was increased, while the proportion of iNKT17 cells was decreased. Conclusion: Dysregulated iNKT cells may be involved in the pathogenesis of psoriasis and secukinumab may play a regulatory role on iNKT cells.

Skin epidermis constitutes the exterior barrier that protects the body from dehydration and environmental assaults. Barrier defects underlie common inflammatory skin diseases, but the molecular mechanisms that maintain barrier integrity and regulate epidermal-immune cell cross-talk in inflamed skin are not fully understood. In this study, we show that skin epithelia-specific deletion of Ovol1, which encodes a skin disease. linked transcriptional repressor, impairs the epidermal barrier and aggravates psoriasis-like skin inflammation in mice in part by enhancing neutrophil accumulation and abscess formation. Through molecular studies, we identify IL-33, a cytokine with known pro-inflammatory and anti-inflammatory activities, and Cxcl1, a neutrophil-attracting chemokine, as potential weak and strong direct targets of Ovol1, respectively. Furthermore, we provide functional evidence that elevated Il33 expression reduces disease severity in imiquimod-treated Ovol1-deficient mice, whereas persistent accumulation and epidermal migration of neutrophils exacerbate it. Collectively, our study uncovers the importance of an epidermally expressed transcription factor that regulates both the integrity of the epidermal barrier and the behavior of neutrophils in psoriasis-like inflammation.

Aberrant RNA splicing in keratinocytes drives inflammatory skin disorders. In the present study, we found that the RNA helicase DDX5 was downregulated in keratinocytes from the inflammatory skin lesions in patients with atopic dermatitis and psoriasis, and that mice with keratinocyte-specific deletion of Ddx5 ( Ddx5 ∆KC ) were more susceptible to cutaneous inflammation. Inhibition of DDX5 expression in keratinocytes was induced by the cytokine interleukin (IL)-17D through activation of the CD93–p38 MAPK–AKT–SMAD2/3 signaling pathway and led to pre-messenger RNA splicing events that favored the production of membrane-bound, intact IL-36 receptor (IL-36R) at the expense of soluble IL-36R (sIL-36R) and to the selective amplification of IL-36R-mediated inflammatory responses and cutaneous inflammation. Restoration of sIL-36R in Ddx5 ∆KC mice with experimental atopic dermatitis or psoriasis suppressed skin inflammation and alleviated the disease phenotypes. These findings indicate that IL-17D modulation of DDX5 expression controls inflammation in keratinocytes during inflammatory skin diseases.

Mesenchymal stem cells (MSCs) have shown great potential in treating autoimmune diseases due to their immunomodulatory capability, which has been verified in both animal experiments and clinical trials. Psoriasis is a chronic and remitting immune-related disease. Limited studies have demonstrated that MSCs might be an effective therapeutic approach for managing psoriasis, whose underlying mechanism remains to be elucidated. In our present study, human umbilical cord-derived MSCs (hUC-MSCs) were subcutaneously injected into mice with imiquimod (IMQ)-induced psoriasis-like skin inflammation to explore the feasibility of this cellular therapy. The severity of psoriasis-like dermatitis was evaluated by cumulative psoriasis area and severity index score and epidermal thickness of skin tissue sections. Flow cytometric analysis was utilized to detect T helper cells, regulatory T cells, and γδ T cells in skin-draining lymph nodes. Real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay were used to assess the expression levels of psoriasis-related cytokines and chemokines in mouse dorsal skin lesions. We discovered that hUC-MSCs drastically diminished the severity of IMQ-induced psoriasis-like dermatitis and suppressed inflammatory cell response. Although the tail vein injection of hUC-MSCs was also effective, it was correlated with higher mortality owing to pulmonary embolism. By comparison, subcutaneous injection with two million hUC-MSCs was identified to be the optimal therapeutic strategy. Furthermore, we uncovered that hUC-MSCs might repress skin inflammation probably through inhibiting interleukin-17-producing γδ T cells. In conclusion, subcutaneous administration of hUC-MSCs might be a promising therapeutic approach for psoriasis. Our findings provide novel insights into the underpinning mechanism of hUC-MSC treatment in the management of psoriasis.

Background: Psoriasis is a T cell-mediated autoimmune skin disease. Accumulating evidence has demonstrated that co-inhibitory receptors (CIRs) play a vital role in regulating T cell-mediated immune response, especially in neoplasm and autoimmunity. However, the immuno-function of CIRs in the development of psoriasis remains unclear. Objective: We investigated the expression of CIRs on the circulating T lymphocytes of psoriasis patients before and after anti-tumor necrosis factor-alpha (TNF-alpha) therapy. Methods: We enrolled 17 patients with moderate-to-severe plaque psoriasis, 17 patients with mild plaque psoriasis, and 18 healthy controls in this study. Fourteen of the moderate-to-severe psoriasis patients were treated with infliximab, a monoclonal antibody against TNF-alpha. Peripheral blood was collected, and peripheral blood mononuclear cells were extracted. The proportion of T cell subsets along with their expression of CIRs, namely T cell immunoreceptor with Ig and ITIM domains (TIGIT), lymphocyte activating gene 3 (LAG-3), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), B and T lymphocyte-associated protein (BTLA), endothelial protein C receptor (PROCR), podoplanin (PDPN), programmed cell death 1 (PD-1), and T cell immunoglobulin mucin family containing molecule 3 (TIM-3), were determined by flow cytometric assay. Results: The moderate-to-severe plaque psoriasis patients had less circulating Tregs, which increased after infliximab treatment. They also had decreased TIGIT, LAG-3 but increased PDPN expression on peripheral CD4+ T cells. Infliximab enhanced TIGIT, LAG-3, CTLA-4 but reduced PROCR expression on circulating CD4+ T cells. Remarkably, both the frequency of circulating Tregs and the expression level of TIGIT on CD4+ T cells at baseline (pre-treatment) negatively correlated with the extent of PASI score reduction benefited from infliximab therapy. Conclusion: Anti-TNF-alpha therapy increased the frequency of Tregs and TIGIT, LAG-3, CTLA-4 expression but reduced PROCR expression on circulating CD4+ T cells in psoriasis patients. The baseline proportion of Tregs and the expression level of TIGIT on circulating CD4+ T cells might serve as predictive markers for the degree of disease remission benefited from infliximab treatment.

Atopic dermatitis (AD) is a common inflammatory dermatologic disease clinically characterized by intense itch, recurrent eczematous lesions, and a chronic or relapsing disease course. Mild-to-moderate AD can be controlled by using moisturizers and topical immunomodulators such as topical corticosteroids and calcineurin inhibitors. If topical therapies fail, phototherapy and systemic immunosuppressant therapies, such as ciclosporin, methotrexate, and azathioprine, can be considered. However, relapse and side effects could still occur. The pathogenesis of AD involves epidermal barrier dysfunction, skin microbiome abnormalities, and cutaneous inflammation. Inflammatory mediators, such as interleukin (IL)-4, IL-13, IL-31, IL-33, IL-17, IL-23, and thymic stromal lymphopoietin, are involved in AD development. Therefore, a series of biological agents targeting these cytokines are promising approaches for treating AD. Dupilumab is the first biological agent approved for the treatment of AD in patients aged 6 years and older in the United States. Tralokinumab, lebrikizumab, and nemolizumab have also been confirmed to have significant efficacy against AD in phase III or IIb clinical trials. Also, fezakinumab was effective in severe AD patients in a phase IIa trial. However, phase II trials of ustekinumab, tezepelumab, etokimab, secukinumab, and omalizumab have failed to meet their primary endpoints. Phase II trials of GBR 830 and KHK 4083 are ongoing. In general, further studies are needed to explore new therapeutic targets and improve the efficacy of biological agents.

To the Editor: Psoriasis affects approximately 125 million people globally. One of the preferred treatments for psoriasis is narrow-band ultraviolet B (NB-UVB) phototherapy. Although NB-UVB is widely used, there is no consistency between different guidelines regarding the ideal starting dose and the dosage increments. Whereas the European S3 guidelines recommend dosage increments of 30%, the American Academy of Dermatology (AAD) guidelines recommend increments of 20%.1Elmets C.A. Lim H.W. Stoff B. et al.Joint American Academy of Dermatology–National Psoriasis Foundation guidelines of care for the management and treatment of psoriasis with phototherapy.J Am Acad Dermatol. 2019; 81: 775-804Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar,2Nast A. Boehncke W.H. Mrowietz U. et al.S3—Guidelines on the treatment of psoriasis vulgaris (English version). Update.J Dtsch Dermatol Ges. 2012; 10: S1-S95Crossref Scopus (234) Google Scholar Although dosimetry needs to be individualized, most phototherapy centers tend to follow regimens recommended in the literature.3Haddican M.M. Bhutani T. McClelland P.B. Koo J.Y.M. Why are there significant differences in published narrowband ultraviolet B dosimetry recommendations? The need for national standardization of phototherapy treatment.J Am Acad Dermatol. 2011; 65: 411-414Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar We aimed to provide relevant recommendations for clinical practice. We compared the efficacy and safety of three incremental dosage regimens of NB-UVB—10%, 20%, and 30%—in patients with psoriasis with skin types III to V. Patients with psoriasis who met the inclusion criteria were invited to participate in this clinical trial (Supplemental Table I, available via Mendeley at https://doi.org/10.17632/hhs8nrpr8x.1). There were 111 patients randomized to receive different dose increment regimens: group 1, 10% dose increment (n = 50); group 2, 20% dose increment (n = 50); or group 3, 30% dose increment (n = 11). Patient disposition is shown in Supplemental Fig 1. Patients received NB-UVB treatment 3 times weekly. Supplemental Table II details the protocol and dosage adjustments. Psoriasis Area and Severity Index (PASI) and static Physician's Global Assessment were measured at baseline and after every 5 sessions. Safety was monitored throughout the study. Differences in baseline characteristics between groups (Supplemental Table III) were not statistically significant. No significant difference was found in the incidence of erythema between group 1 and group 2; however, the proportion of patients developing erythema in group 3 (72.7%) was much higher than in group 1 (20.4%) and group 2 (20.8%) (Table I). Although the S3 guidelines recommend an increment of 30%, we do not consider it advisable in skin types III to V.2Nast A. Boehncke W.H. Mrowietz U. et al.S3—Guidelines on the treatment of psoriasis vulgaris (English version). Update.J Dtsch Dermatol Ges. 2012; 10: S1-S95Crossref Scopus (234) Google ScholarTable IComparison of the rate of erythemaErythema response 48 h after the last treatment∗Data are presented as number (%).Group 1 (n = 49)Group 2 (n = 48)Group 3 (n = 11)0 = none37 (75.5)38 (79.2)3 (27.3)1 = mild5 (10.2)6 (12.5)1 (9.1)2 = moderate4 (8.2)4 (8.3)3 (27.3)3 = severe1 (2.0)0 (0.0)4 (36.3)Total10 (20.4)10 (20.8)8 (72.7)Group 1, 10% dose increment; group 2, 20% dose increment; group 3, 30% dose increment.Patients who withdrew before first treatment were excluded.∗ Data are presented as number (%). Open table in a new tab Group 1, 10% dose increment; group 2, 20% dose increment; group 3, 30% dose increment. Patients who withdrew before first treatment were excluded. Our findings support previous data suggesting that NB-UVB is highly effective for treatment of plaque psoriasis. The proportion of patients achieving PASI 75 and PASI 90 treatment responses at the completion of session 30 were similar in group 1 and group 2 (PASI 75: 59.2% vs 70.8%, respectively, P = .23; and PASI 90: 24.5% vs. 29.2%, respectively, P = .60; Supplemental Table IV). However, treatment response was significantly faster in group 2 than in group 1 (P = .026; Fig 1). One interesting finding was that satisfactory treatment response was more likely in those with a history of psoriasis remission in summer than in those without such a history (PASI 75 rate: 70.4% vs 58.1%, respectively, P = .21; and PASI 90 rate: 35.2% vs 16.3%, respectively, P = .04; Supplemental Table V). Previous studies have reported that sunbathing at the Dead Sea is effective.4Kudish A.I. Harari M. Evseev E.G. The measurement and analysis of normal incidence solar UVB radiation and its application to the photoclimatherapy protocol for psoriasis at the Dead Sea, Israel.Photochem Photobiol. 2011; 87: 215-222Crossref PubMed Scopus (16) Google Scholar Thus, we speculate that patients who tend to improve in the summer may be more sensitive to UVB therapy; thus, such a history could be used as a predictor of response. In conclusion, this small single-center study shows that a 20% incremental dose regimen results in a faster response for psoriasis, without increasing the risk of adverse events in III to V skin types.

Psoriasis is a common inflammatory skin disease characterized by aberrant inflammation and epidermal hyperplasia. Molecular mechanisms that regulate psoriasis-like skin inflammation remain to be fully understood. Here, we show that the expression of Ovol1 (encoding ovo-like 1 transcription factor) is upregulated in psoriatic skin, and its deletion results in aggravated psoriasis-like skin symptoms following stimulation with imiquimod. Using bulk and single-cell RNA sequencing, we identify molecular changes in the epidermal, fibroblast, and immune cells of Ovol1-deficient skin that reflect an altered course of epidermal differentiation and enhanced inflammatory responses. Furthermore, we provide evidence for excessive full-length IL-1α signaling in the microenvironment of imiquimod-treated Ovol1-deficient skin that functionally contributes to immune cell infiltration and epidermal hyperplasia. Collectively, our study uncovers a protective role for OVOL1 in curtailing psoriasis-like inflammation and the associated skin pathology.

Psoriasis is a chronic inflammatory skin disease with unclear pathogenesis. Interleukin-33 (IL-33) is highly expressed in patients with psoriasis, but its role in psoriasis is unknown. The aim of this study was to investigate the possible role of IL-33 in the pathogenesis and treatment of psoriasis. IL-33 expression was determined using enzyme-linked immunosorbent assay, real-time fluorescent quantitative polymerase chain reaction and immunohistochemical staining. CD4+ T cells were sorted using magnetic beads and treated with or without IL-33. Imiquimod (IMQ) was used to induce psoriatic inflammation in mice. The frequency of immune cells was determined using flow cytometry. The cytokine level in mouse skin was measured using cytometric bead array. Our results showed that IL-33 was highly expressed in the lesional skin and serum of patients with moderate-to-severe plaque psoriasis. IL-33 inhibited the expression of IL-17 in CD4+ T cells of psoriasis patients. Subcutaneous injection of IL-33 alleviated the IMQ-induced psoriatic inflammation in mice, reduced tumor necrosis factor-α and IL-23 expression, and decreased the proportion of T helper type 17 (Th17) cells in the skin-draining lymph nodes in the mice. Our results suggest that IL-33 plays a protective role in the pathogenesis of psoriasis by suppressing Th17 cell differentiation and function. The potential therapeutic effect of IL-33 in treating psoriasis warrants further investigation.

BACKGROUND:Previous psoriasis studies have mostly focused on skin-related immunology, but the exact mechanisms remain elusive. Clinical evidence, such as higher morbidity among obese individuals and emotional factors, indicate that psoriasis is a complex systemic disease. High-throughput transcriptome analysis provides an effective method to comprehensively assess the disease.OBJECTIVE:The present study is aiming to understand transcriptome changes of clinical psoriasis skins and comprehensively assess the diseases using pathways analysis.METHODS:We performed transcriptome sequence of clinical psoriatic samples. Biological pathway analyses were conducted using differentially expressed RNAs, as well as identified competing endogenous RNAs (ceRNAs). qRT-PCR and histological immunofluorescence staining was conducted to verify the differentially expressed RNAs (DE_RNAs) and the three important enriched biological pathways.RESULTS:Numerous DE_RNAs were identified between psoriasis patients and healthy people. Functional analysis indicated PPAR-fatty acids metabolism pathways, neural-hormone regulations, circadian entrainment were the three mostly appeared pathways. For PPAR-fatty acids metabolism pathways, the expression of seven randomly selected genes, including ACSBG1, ACOT2), CYP27A1, ELOVL3, FABP7, FADS2 and PPARG were all significantly decreased in psoriasis lesions. For neural-hormone regulation pathways, the expression of CFL1, EPHA2, HRAS were all significantly upregulated in psoriasis lesions. While the expression of four randomly selected genes from circadian entrainment pathways, including CRY2, PER3, NR1D1 and RORC were all significantly downregulated. Histological immunofluorescence staining of FADS2, EPHA2 and CRY2 were consistent with their genes' expressions.CONCLUSION:Our results revealed transcriptome changes of psoriasis, and indicated three important pathways involved in psoriasis, including PPAR-fatty acids metabolism pathways, neural-hormone regulations, circadian entrainment.

Background: Psoriasis is a chronic immune-mediated inflammatory skin disease, with over-activated interleukin (IL)-17-producing CD4+ T cells (Th17) and repressed regulatory T (Treg) cells. IL-21 is a Th17-related cytokine and plays an important role in the pathogenesis of psoriasis. However, the mechanism by which IL-21 affects the pathogenic progress of psoriasis remains poorly understood. Methods: IL-21 and IL-21 receptor (IL-21R) expression in normal and psoriatic lesional skin were determined by immumohistochemical staining, immunofluorescence staining, and western blotting. The levels of IL-21, IL-17A, and IL-22 in the culture supernatants were measured by enzyme-linked immunosorbent assay (ELISA). The level of IL-10 in the culture supernatants was measured by cytometric bead array (CBA). The mRNA expression levels were assessed by quantitative polymerase chain reaction (qPCR). CD4+ T cells were isolated from the peripheral blood mononuclear cells (PBMCs) from the psoriasis patients and healthy individuals and then treated with or without IL-21 for 3 days. The proportions of Th17 and Treg cells were determined by flow cytometric analysis. Results: IL-21 and IL-21R were highly expressed in the lesional skin and peripheral blood of psoriasis patients. IL-21 promoted CD4+ T cells proliferation and Th17 cells differentiation and inhibiting Treg cells differentiation by upregulating RORγt expression and downregulating Foxp3 expression, with increased expression and secretion of IL-17A and IL-22. The proportion of Treg cells was negatively correlated with that of Th17 cells in psoriasis patients. Conclusion: Our results suggest that IL-21 may promote psoriatic inflammation by inducing imbalance in Th17 and Treg cell populations.

Background: Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyper proliferation. Ginsenoside compound K (CK), a bioactive metabolite of ginseng, modulates various skin disorders with an impact on keratinocyte biology. However, the effect of Ginsenoside CK in psoriasis has not been explored. Objective: Our aim was to investigate whether ginsenoside CK could affect the homeostasis of keratinocytes and their expression of psoriasis-associated antimicrobial protein regenerating islet-derived protein 3-alpha (REG3A) and its murine ortholog RegIII gamma. We further explored the therapeutic potential of ginsenoside CK in imiquimod (IMQ)-induced psoriasis-like dermatitis. Methods: The effects of ginsenoside CK in cell growth and apoptosis of human keratinocytes were measured by MTT assay and flow cytometry, respectively. Bax levels were evaluated by Western blot in HaCaT cells following ginsenoside CK stimulation. REG3A levels were assessed by RT-PCR and Western blot in human keratinocytes following interleukin (IL)-36 gamma and ginsenoside CK co-simulation. Utilizing IMQ-induced psoriasis mouse model, the therapeutic effects of 0.1% and 1% ginsenoside CK cream were assessed by skin thicknesses and histological examinations, and RegIII gamma level in the lesional skin was detected by Western blot and immunofluorescence. Results: Ginsenoside CK prohibited human keratinocyte proliferation but did not affect their apoptosis. Moreover, it inhibited 1L-36 gamma-induced REG3A expression in HaCaT cells. Ginsenoside CK alleviated imiquimod-induced psoriasis-like hyperkeratosis and reduced RegIII gamma expression in the keratinocytes from lesional skin. Conclusion: Ginsenoside CK ameliorated IMQ-induced psoriasis-like dermatitis possibly through inhibiting REG3A/RegIII gamma expression in keratinocytes, which highlighted a therapeutic potential of ginsenoside CK in psoriasis. (C) 2019 Elsevier Inc. All rights reserved.

Phaeohyphomycosis, caused by opportunistic rare fungi, has increasingly been reported in diabetic and immunosuppressed patients. Pyrenochaeta unguis-hominis (P. unguis-hominis), a member of the dematiaceae group, has been identified to cause human nail infection. We report a rare case of cutaneous phaeohyphomycosis in a diabetic female caused by P. unguis-hominis.

Numerous biologics are currently licensed for the treatment of psoriasis, including new drugs targeting interleukin-17 (IL-17) and interleukin-23 (IL-23). This meta-analysis evaluated the short-term (12-16 weeks) efficacy and safety of biologics targeting IL-17 and IL-23 in the treatment of moderate-to-severe plaque psoriasis. Twenty-one randomized clinical trials met the defined inclusion criteria. Our results showed that Ixekizumab (160 mg wk0 + 80 mg q2w) had the greatest probability of achieving both PASI 75 (RR 21.32, 95% CI 15.48-29.36, P < 0.00001) and PASI 90 response (RR 59.76, 95% CI 32.41-110.19, P < 0.00001) at the primary endpoint times, followed by Ustekinumab and Secukinumab. Regarding the safety profile, Tildtakizumab (200 mg, q4w) was safest (RR 0.88, 95% CI 0.78-0.99, P = 0.04), while Ixekizumab (160 mg wk0 + 80 mg q2w) showed highest risk for one or more AE (RR 1.26, 95% CI 1.15-1.38, P < 0.00001). However, there was no significant difference between the two biologics regarding one or more SAEs. Comparing to the biologics targeting IL-23, the pooled effect size favored the biological agents targeting IL-17 in terms of the PASI 75 (PASI 75: RR 17.28, 95% CI 14.51-20.58, P < 0.00001) and PASI 90 (RR 37.19, 95% CI 26.91-51.41, P < 0.00001). The rate of overall AEs was significantly higher (P < 0.00001) in biologics targeting the IL-17 (RR 1.18, 95% CI 1.12-1.24, P < 0.00001) compared to biologics targeting IL-23 (RR 0.97, 95% CI 0.91-1.04, P = 0.44), and with respect to one or more SAEs, no difference was seen between biologics targeting IL-17 and IL-23. This meta-analysis found that Ixekizumab was the most effective short-term treatment, but was ranked as the most risk therapeutic choice among the biologics involved in this study, while Tildtakizumab was the best alternative in the case of safety. Furthermore, it demonstrated that biologics inhibiting IL-17 were superior to biologics targeting IL-23 in terms of the efficacy, but posed higher risk at the same time. This study might help the clinicians and guideline developers to choose the optimal one among these biologics for the treatment of moderate-to-severe plaque psoriasis.

Psoriasis is an immune-mediated polygenic inherited skin disease. Many biologic agents have been approved for the treatment of moderate-to-severe plaque psoriasis. The most commonly utilized biologics include TNF-α antagonists (etanercept, infliximab, and adalimumab), IL-12/23P40 antagonist (ustekinumab), IL-23P19 antagonist (guselkumab), IL-17A antagonist (secukinumab and ixekizumab), and IL-17RA antagonist (brodalumab). However, some patients may fail to respond well to their first biologic agent. Reasons for failure include primary failure (lack of initial efficacy), secondary failure (loss of efficacy over time) or the development of adverse effects. For patients desiring maximum skin clearance and better quality of life, switching to a second biologic agent might be a worthwhile option. This review discusses recent clinical studies on switching therapies in treating psoriasis, and found that switching biologic agents can significantly improve outcomes for patients. Some clinical guidelines are also discussed. This research provides some advice on establishing individualized treatment regimens based on clinical needs and pharmacologic characteristics.

Psoriasis is a chronic inflammatory disease of the skin which can occur at any age-group. Psoriasis in childhood is not uncommon and has genetic susceptibility but usually, an environmental trigger such as infection is thought to initiate the disease process. Pediatric psoriasis has profound effects on both physical and psychosocial health of the patient. Treatment of mild psoriasis can be done with topical therapies but those which do not respond to topical therapies can be treated with phototherapy and systemic therapies. The use of systemic therapies in childhood is mainly based on the published data, case series, expert opinion and the experience as there is the lack of controlled trials in the age group. Based on the experience retinoids are probably the second line drugs for the treatment of pediatric psoriasis which do not respond to topical therapies and phototherapy. Using acitretin in a low dose and with proper physical examinations and laboratory investigations will reduce the hazard of potential serious adverse events. This article gives the review of the use of acitretin in pediatric psoriasis.