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The occurrence of pruritus in psoriasis was previously underestimated but is a significant burden. Secukinumab (SEC), a monoclonal anti-interleukin-17A antibody, efficiently controls signs of psoriasis, but the effect on pruritus and cutaneous neuroanatomy remained unknown. The primary objective of this study (NCT02362789) was to evaluate the superiority of SEC treatment vs placebo on pruritus intensity (visual analogue scale; VAS). Furthermore, the treatment-dependent course of pruritus in association with absolute Psoriasis Area Severity Index (PASI) score, as well as cutaneous histopathology and neuroanatomy, was assessed. Open-label SEC 300 mg s.c. was administered regularly until week 16. Patients who reached a ≥ 98% PASI reduction (PASI ≥ 98) were randomized to receive either placebo or SEC up to week 32. Punch biopsies were collected from lesional psoriatic (baseline, weeks 16 and 32) and non-lesional (baseline) skin for histopathological and neuroanatomical analyses. VAS scores improved significantly after open-label SEC treatment but relapsed upon placebo (29.92 ± 33.8) compared with SEC (12.30 ± 22.6; p = 0.036). After SEC-dependent improvement in PASI, histopathology, marker expression and neuroanatomy, relapse was observed with treatment discontinuation in all parameters except neuroanatomy. SEC was superior to placebo by efficiently controlling reduced pruritus intensity, clinically normalizing skin lesions, and reversing histopathological abnormalities. The neuroanatomy recovered upon SEC and remained stable even after withdrawal.

Psoriasis is a prevalent, inflammatory skin disease without cure. Further research is required to unravel dysregulated processes and develop new therapeutic interventions. The lack of suitable in vivo and in vitro preclinical models is an impediment in the psoriasis research. Recently, the development of 3D skin models has progressed including replicas with disease-like features. To investigate the use of in vitro models as preclinical test tools, the study focused on treatment responses of 3D skin replicas. Cytokine-priming of skin organoids induced psoriatic features like inflammation, antimicrobial peptides (AMP), hyperproliferation and impaired differentiation. Topical application of dexamethasone (DEX) or celastrol (CEL), a natural anti-inflammatory compound reduced the secretion of pro-inflammatory cytokines. DEX and CEL decreased the gene expression of inflammatory mediators. DEX barely affected the psoriatic AMP transcription but CEL downregulated psoriasis-driven AMP genes. Subcutaneous application of adalimumab (ADM) or bimekizumab (BMM) showed anti-psoriatic effects via protein induction of the differentiation marker keratin-10. Dual blockage of TNF-α and IL-17A repressed the inflammatory psoriasis phenotype. BMM inhibited the psoriatic expression of AMP genes and induced KRT10 and cell-cell contact genes. The present in vitro model provides a 3D environment with in vivo-like cutaneous responses and represents a promising tool for preclinical investigations., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Objective: This post hoc analysis compared the immunogenicity of the biosimilar adalimumab-adbm (Cyltezo) with the adalimumab reference product (RP; Humira) across indications, including rheumatoid arthritis (RA), Crohn's disease (CD) and plaque psoriasis (PsO), and by patient sex in the VOLTAIRE trials programme., Methods: In each active-comparator randomised controlled trial (RCT), immunogenicity was assessed at various time points by the proportion of patients with antidrug antibodies (ADAs) and neutralising antibodies (nAbs), using acid dissociation followed by electrochemiluminescence assay. Assay sensitivity was 50 ng/mL, and drug tolerance was ≥30 µg/mL (free drug) at the low positive control level., Results: Minor differences in immunogenicity parameters (ADAs, ADA titres and nAbs) were evident between adalimumab-adbm and adalimumab RP across these three immune-mediated inflammatory diseases (IMIDs). The proportion of ADA-positive and nAb-positive patients increased from baseline over time in all three RCTs, as expected, and was similar in the RA and CD RCTs but with higher numbers of ADA-positive and nAb-positive patients reported in the PsO trial. Subgroup analysis by patient sex showed the same trend., Conclusions: Differences among the RCTs may partially be explained by concomitant background therapy (methotrexate) in the RA trial, stable doses of azathioprine, 6-mercaptopurine or methotrexate in 36% of patients with CD and absence of background therapy in the PsO RCT. The analyses further confirm the biosimilarity of adalimumab-adbm with the adalimumab RP across IMIDs and provide supporting evidence that adalimumab-adbm is an interchangeable biosimilar with consistent clinical results in patients originally treated with the RP., Trial Registration Numbers: VOLTAIRE-RA (NCT02137226; EudraCT 2012-002945-40); VOLTAIRE-CD (NCT02871635; EudraCT 2016-000612-14); VOLTAIRE-PsO (NCT02850965; EudraCT 2016-000613-79)., Competing Interests: Competing interests: VS reports consulting for AbbVie, Amgen, Aria, AstraZeneca, Bayer, Bioventus, BlackRock, BMS, Boehringer Ingelheim, Celltrion, ChemoCentryx, Equillium, Gilead, Genentech/Roche, Glenmark, GSK, Horizon, Inmedix, Janssen, Kiniksa, Kypha, Lilly, Merck, MiMedx, Novartis, Pfizer, Priovant, Regeneron, Rheos, R-Pharma, Samsung, Sandoz, Sanofi, Scipher, Setpoint, Sorrento, Spherix and Tonix. SB reports previous employment by Boehringer Ingelheim Pharmaceuticals. DM reports previous employment by Boehringer Ingelheim Pharmaceuticals., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Treating psoriasis presents a major clinical challenge because of the limitations associated with traditional topical glucocorticoid therapy. This study introduced a drug delivery system utilizing zinc-doped mesoporous silica nanoparticle (Zn-MSN) and microneedle (MN), designed to enhance drug utilization for prolonged anti-inflammatory and anti-itch effects. The MN system facilitated the transdermal delivery of betamethasone dipropionate (BD), allowing its slow release. The BD@Zn-MSN-MN system promoted the polarization of macrophages towards the anti-inflammatory M2 phenotype, achieving superior anti-inflammatory effects compared to the clinically used BD cream. Additionally, this study demonstrated that BD@Zn-MSN-MN could further alleviate itching in psoriasis-afflicted mice by decreasing the excitability of the transient receptor potential vanilloid V1 (TRPV1) ion channel positive neurons and reducing the release of calcitonin gene-related peptide (CGRP) in the dorsal root ganglion (DRG). These findings offer new insights and effective therapeutic options for the future design of transdermal drug delivery for psoriasis., Competing Interests: Declarations Ethics approval and consent to participate The animal experiments were approved by the Ethics Committee for Experimental Use of Animals of the Shanghai Jiao Tong University School of Medicine (approval code: #SYXK-2013-0050). Consent for publication All authors agree for publication. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Psoriasis is chronic immune-mediated inflammatory disorder characterized by various comorbidities, erythematous plaques with silvery scale which can lead to psoriatic arthritis. The phosphodiesterase 4 (PDE4) protein is a potential drug target to control Psoriasis. In the current study, pharmacophore-based virtual screening of Diversity library of ChemDiv database was first performed, and then the screened hits were docked to the active site of PDE4 to choose the best binding modes. Forty-six hits generated during the virtual screening were prepared and docked to the PDE4 receptor by SP docking module of glide. The binding affinities of the selected hits were calculated by molecular docking and based on the affinities, ten hits were selected for the bioactivity scores prediction and ADMET analysis. Based on the ADMET profiling, four hits D356-2630, C700-2058, G842-0420 and F403-0203 were processed to MD simulations for stability analysis. The outcomes showed that these compounds showed strong binding with proteins with better binding free energies. Based on the results of our study, we proposed that these hits can function as lead in the biological assays and in vitro studies are required to develop the novel drug candidates., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Alanzi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Psoriasis is a chronic, inflammatory skin disease characterized by a dysregulated immune response and systemic inflammation. Up to one-third of patients with psoriasis have psoriatic arthritis (PsA). Targeted treatment with antibodies neutralizing tumor necrosis factor can ameliorate both diseases. We here explored the impact of long-term infliximab treatment on the composition and activity status of circulating immune cells involved in chronic skin and joint inflammation. Immune cells were analyzed by multicolor flow cytometry. We measured markers of immune activation in peripheral blood mononuclear cell populations in 24 infliximab-treated patients with psoriasis/PsA compared to 32 healthy controls. We observed a significant decrease in the frequency of both peripheral natural killer (NK) cells and their subset CD56dimCD16+ NK cells in PsA compared to healthy controls and patients with psoriasis. The latter had a strong-positive correlation with psoriasis area severity index (PASI) in these patients, while CD56brightCD16- NK cells were negatively correlated with PASI. In addition, we observed an upregulation of CD69+ intermediate CD14+CD16+ and CD69+ classical CD14+CD16- monocytes in PsA and increased activity of CD38+ intermediate CD14+CD16+ monocytes in patients with psoriasis. Compared to healthy controls, psoriasis patients demonstrated shifts of the three B-cell subsets with a decrease in transitional CD27-CD38high B cells. Our exploratory study indicates a preserved pathophysiological process including continuous systemic inflammation despite clinical stability of the patients treated with infliximab., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology.)

Background: Psoriasis is an autoimmune skin condition characterized by hyperproliferation of keratinocytes and chronic immune responses. Gypenosides (Gyp) exhibits anti-proliferative and anti-inflammatory effects on different diseases. However, its functioning and mechanism of Gyp on psoriasis remains unknown., Objective: To explore the effect and mechanism of Gyp on psoriasis., Material and Methods: The impact and mechanism of Gyp on psoriasis in vitro and in vivo were probed through cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay, reverse transcription quantitative polymerase chain reaction, hematoxylin and eosin staining, enzyme-linked immunosorbent serologic assay, immunofluorescence, and Western Blotting assays., Results: Gyp inhibited cell proliferation and the release of inflammatory cytokinesin interleukin (IL-22)-induced spontaneously transformed human aneuploid immortal keratinocyte cell line (HaCaT). In addition, Gyp demonstrated enhancement in erythema and scaling as well as reductions in the thickness of epidermal layers, release of inflammatory factors, and Ki-67 (a nuclear protein) level in imiquimod (IMQ)-induced mice. Mechanistically, Gyp upregulated nuclear factor erythroid 2-related factor 2 (Nrf-2) expression and diminished the level of p-p65/p65 and p-STAT3/STAT3 in skin tissues from IMQ-induced mice and IL-22-induced HaCaT cells, which were reversed with the application of ML385, an inhibitor of Nrf2. In addition, the administration of ML385 reversed decrease in cell viability and reduced the expressions of IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) in IL-22-induced HaCaT cells caused by Gyp., Conclusion: In summary, Gyp reduced excessive cell growth and inflammation in psoriasis by suppressing nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) through activation of Nrf2.

Objectives: To evaluate health-related quality of life perceived by patients with the most prevalent immune-mediated inflammatory diseases in Spain: inflammatory bowel disease (IBD), psoriasis (Ps), psoriatic arthritis (AP), rheumatoid arthritis (RA), and spondyloarthropathies (SpAs), and to determine the factors that influence patient quality of life., Methods: The SACVINFA study (SA = satisfaction, CV = quality of life, IN = immune-mediated, FA = pharmacy) consisted of an observational study conducted in 4 hospitals in the Community of Madrid. A cross-sectional analysis was made of adult patients diagnosed with an immune-mediated inflammatory disease who attended the Pharmacy Service. Quality of life was assessed using the EQ-5D-5L questionnaire (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and specific questionnaires: SIBDQ-9, DLQI, PsAQoL, QoL-RA and ASQoL., Results: A total of 578 patients were analyzed (inflammatory bowel disease = 25.3%; psoriasis = 19.7%; spondyloarthropathies = 18.7%; rheumatoid arthritis = 18.5%; psoriatic arthritis = 17.8%). The mean age (SD) was 49.8 (12.3) years and 50.7% were male. The average score (SD) for the global EQ-5D- 5 L was 0.771 (0.2) and the mean (SD) visual analogue scale score was 71.5 (20.0). Type of immune-mediated inflammatory diseases was associated with differences in quality of life showing psoriasis and inflammatory bowel disease higher values of EQ-5D-5L than psoriatic arthritis, rheumatoid arthritis and spondyloarthropathies, p < 0,05 in all comparisons. Patients with RA, IBD, and Ps achieved 70% of the maximum score, while patients with PsA and SpAs did not reach 50% of the maximum possible score. Female gender, a state of moderate/severe disease severity, an older age and a higher number of previous treatments were correlated with worse quality of life. Conversely, persistence to current treatment correlated with better quality of life., Conclusions: Patients with immune-mediated inflammatory diseases have markedly affected quality of life, mainly in the pain/discomfort dimension, especially in those immune-mediated inflammatory diseases with a rheumatological component., (Copyright © 2024 Sociedad Española de Farmacia Hospitalaria (S.E.F.H). Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Psoriasis (PSO) poses a global health threat. The current research challenge in PSO is relapse. Liquiritin (LIQ), a major active compound from Glycyrrhiza inflata Batalin, has multiple pharmacological properties, including anti-inflammatory and anti-proliferative. Nonetheless, the precise mechanisms underlying LIQ's therapeutic actions in PSO and prevention abilities remain elusive., Purpose: The present study aimed to delve into the potential to treat and prevent PSO and the mechanism of LIQ., Methods: The anti-inflammatory and anti-proliferative effects of LIQ were studied in vitro with the HaCaT cell line. Then, Transcriptional analysis and bioinformatic analysis were used to determine the internal associations of the target set. Subsequently, functional experiment, luciferase report assay, ChIP-PCR, and immunohistochemical validation of clinical samples were performed to investigate the mechanism of LIQ. Finally, the anti-psoriatic effects and prevention abilities of LIQ were verified in vivo with imiquimod (IMQ)-induced PSO-like mouse models., Results: Here, we identified differentially expressed genes in LIQ-stimulated HaCaT cells and Retinol-Binding Protein 3 (RBP3) as the core target, whereas YY1 was a predicted upstream transcription factor of RBP3. The YY1/RBP3 axis was obviously altered after administering LIQ at optimal doses of 20 μM in vitro and 100 µg/ml in vivo. LIQ can significantly inhibit the progression of PSO in vivo. Notably, LIQ also prevented the relapse of psoriatic lesions induced by the second round of low-dose IMQ. Mechanistically, we observed that LIQ could increase the promotion of YY1 for RBP3 by enhancing the binding affinity between them., Conclusion: These findings revealed that the YY1/RBP3 axis is a potential psoriatic target, and LIQ is a promising and innovative therapeutic candidate for the treatment and prevention of PSO., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background Psoriasis is a chronic, inflammatory, systemic disease with predominant manifestations in the skin and joints impairing patient's quality of life. A proportion of patients have frequent severe disease exacerbations requiring repeated systemic treatments. There is a scarcity of literature evaluating the role of systemic maintenance therapy in psoriasis patients in preventing such frequent disease flares. Objective To evaluate the efficacy and safety of weekend cyclosporine treatment (WCT) as maintenance therapy in moderate to severe chronic plaque psoriasis patients for the prevention of frequent disease exacerbations. Methods In this retrospective cohort study, 22 psoriasis patients with a history of frequent disease exacerbations (≥ 3 in the last 1 year) who were administered WCT (group A) were compared with the same number of matched patients (age and gender) not on WCT or any systemic maintenance therapy (group B). Results Four patients (18.2%) in group A had disease exacerbations which was significantly lower (p = 0.00, Fisher's exact test) as compared to 21 patients (95.5%) in group B during the study period. Also, patients in group A had significantly lower number of overall exacerbations [mean ± SD: 0.23 ± 0.53 vs 2.95 ± 1.43) p = 0.00, Mann-Whitney U test] as compared to group B. Four (9.1%) patients in group A encountered adverse effects (acneiform eruptions - two, mild gingival hyperplasia - one, myalgia - one) as compared to three (acneiform eruptions - two, headache - one) in group B (p = 1.00). Conclusion WCT significantly reduced the number of disease exacerbations and is a safe and effective mode of maintenance therapy in such subset of psoriasis patients.

Background: The efficacy and safety of secukinumab in psoriasis patients has been demonstrated in randomized controlled clinical trials., Objectives: The authors aimed to evaluate the efficacy and safety of secukinumab in plaque psoriasis patients followed in our clinic., Methods: Data from 101 plaque psoriasis patients who received at least 16 weeks of secukinumab treatment between June 2018 and June 2023 were retrospectively analyzed., Results: Fifty-three (53%) of the patients were bionaive. PASI-75, -90, -100 response rates were 72%, 50%, 30% respectively at week 16 in all patients. PASI-75 and -90 responses were higher in naive patients at weeks 16 and 28 (p < 0.001, p < 0.001, p < 0.01, p = 0.01, respectively). The percentage of patients with PASI ≤ 1, ≤ 3, ≤ 5 were 50%, 77%, and 92%, respectively at week 16. They were higher in the naive group than in nonnaive group at weeks 16 and 28 (p = 0.02, p < 0.01, p = 0.05, p = 0.07, p < 0.01, p = 0.03, respectively). At week 52, PASI-75, -90, -100 responses were significantly lower in smoking patients (p = 0.04, p = 0.03, p < 0.01, respectively). The mean duration of secukinumab treatment was 19.80 ± 12.76 months. Secukinumab was discontinued 14 (26.4%) naive patients and 28 (58.3%) nonnaive patients at one occasion during treatment (p < 0.001). The most common adverse event in patients was mucocutaneous candida infection (8%). No hepatitis B or C reactivation and no active or reactivation tuberculosis were observed in any of the patients during the follow-up period., Study Limitations: This is a single-center retrospective study with relatively few patients including only the Turkish population., Conclusion: Secukinumab seems to be effective in plaque psoriasis, particularly in bionaive and non-smokers. Moreover, it is safe in patients with inactive hepatitis or tuberculosis., (Copyright © 2024 Sociedade Brasileira de Dermatologia. Published by Elsevier España, S.L.U. All rights reserved.)

There are comorbidities and complications in atopic dermatitis and psoriasis that often occur after the appearance of skin inflammation. Statistically, data show that patients with psoriasis and atopic dermatitis have a shorter life expectancy than patients without psoriatic dermatitis, due to the occurrence of arteriosclerosis, myocardial infarction, and cerebral infarction. Many types of skin inflammation are treated with various antibody preparations, and marked improvement in patients' quality of life can be achieved. The next theme is to understand the pathogenesis of arteriosclerosis, myocardial infarction, stroke, and other complications associated with dermatitis and to find treatments and drugs to reduce their occurrence. The skin, a crucial immune organ, generates large amounts of inflammatory cytokines in response to various stimuli, leading to systemic inflammation and potential damage to internal organs. The link between inflammatory skin conditions like psoriasis and atopic dermatitis with serious health complications such as vascular disorders and systemic amyloidosis has been increasingly recognized. In psoriasis, biological treatments targeting Interleukin (IL)-17A, a key cytokine, have shown promise in reducing cardiovascular risks. Recent developments include treatments that target both IL-17A and IL-17F in the psoriasis field, though each cytokine's impact on internal organ damage is still under debate. Among visceral complications secondary to dermatitis, systemic amyloidosis and atherosclerosis have been reported to be controlled by suppressing IL-17 in the early stages of dermatitis. Still, it remains unclear whether suppressing IL-17 prevents organ damage in the late stages of persistent severe dermatitis. A study using a long-lasting dermatitis mouse model that overexpressed human caspase-1 in keratinocytes (Kcasp1Tg) investigated the effects of deleting IL-17A and IL-17F on visceral complications. Cross-mating Kcasp1Tg with IL-17A-, IL-17F-, and IL-17AF-deficient mice assessed the skin and visceral organs histologically, and RT-PCR analysis of aortic sclerosis markers was performed. Despite less improvement in dermatitis, deletion of IL-17A in Kcasp1Tg mice showed promising results in reducing multiple organ amyloidosis. On the other hand, the effect was observed in both IL-17A and IL-17F deleted mice for aortic sclerosis. The inhibition of IL-17A and IL-17F was suggested to reduce the risk of developing comorbidities in internal organs. IL-17A and IL-17F were found to act similarly or produce very different results, depending on the organ.

Introduction: Psoriasis, a persistent skin condition caused by the disorder of the immune system, impacts approximately 1.25 million individuals globally. Nevertheless, the presence of adverse effects in conventional clinical drugs necessitates further exploration of novel medications or combination therapies to mitigate these reactions and enhance their effectiveness., Methods: Hence, our intention here in this paper is to utilize the lipid nanoparticle delivery system for overcoming the volatility and hydrophobic properties of α-pinene, a naturally occurring compound renowned for its anti-inflammatory and antiviral effects, and further explore its potential pharmacological applications both in vitro and in vivo ., Results: The production of α-pinene lipid nanoparticles (APLNs) was achieved through the utilization of high pressure homogenization methods. APLNs was successfully fabricated with enhanced stability and water solubility. Meanwhile, the application of APLNs could drastically reduce the expression of lipopolysaccharide (LPS)-induced inflammation-related factors in THP-1 cells. Administration of APLNs to a mouse model of auricular swelling could effectively reduce redness and swelling in the auricles of mice as well. Furthermore, APLNs were also found to alleviate skin damage in mice with Imiquimod (IMQ)-induced psoriasis model, as well as decrease the levels of psoriasis-related protein nuclear factor kappa-B (NF-κB) and interleukin-17 (IL-17), interleukin-23 (IL-23), and other inflammation-related cytokines. More importantly, utilization of APLNs successfully mitigated the systemic inflammatory reactions in mice, resulting in the reduction of spleen-to-body ratio (wt%) and of inflammatory cytokines' expression in the serum., Discussion: Overall, our results suggest that with the help of lipid nanoparticle encapsulation, APLNs possess a better pharmacological effect in anti-inflammation and could potentially serve as an anti-psoriasis drug., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Liang, Zhao, Chen, Zhu, Duan, Zou, Huang, Li and Zhang.)

Background: Radix Rehmanniae (RR) plays an important role in treating psoriasis. However, the active compounds of RR and potential mechanisms are unclear. The current study was designed to investigate the potential active ingredients, targets, and mechanisms of RR in treating psoriasis through network pharmacology, molecular docking, and vitro experiments., Methods: Initially, the TCMSP database and literature retrieval were used to access the active ingredients of RR. The psoriasis target proteins were obtained from Therapeutic Target Database, OMIM, GeneCards, and DrugBank databases. The target proteins were then converted into target genes using Uniprot. Secondly, overlapping genes were obtained through Venn online tool. Then, protein-protein interactions network diagram is finished by STRING database. Next, Cytoscape software was used to acquire the top 10 hub proteins; gene ontology and Kyoto encyclopedia of genes and genomes enrichment analysis were then used to predict possible mechanisms. Afterwards, molecular docking validation of the active ingredients with the main targets was performed by AutoDock software. Finally, lipopolysaccharides induced RAW264.7, to assess the effects and molecular mechanisms by MTT, RT-qPCR, and Western blot assays., Results: Overall, there are 20 effective compounds and 33 targets involved in biological processes including apoptosis, intracellular signaling, vasodilation, and mitogen-activated protein kinase (MAPK) signaling cascade. The docking results showed strong binding capacity between the active ingredients and targets. We verified aucubin as the key active ingredient, tumor necrosis factor α, and IL6 as the core targets, and focused on the p38MAPK protein pathway. Cellular experiments showed that aucubin down-regulated the phosphorylated p38MAP protein and reduced the expression of tumor necrosis factor α mRNA, IL6 mRNA, and IL1βmRNA., Conclusion: In summary, RR is featured with multicomponent, multi-target, and multi-pathway in treating psoriasis; the preliminary mechanism may be associated with the down-regulation of p38MAPK phosphorylation and curbing the expression of inflammatory factor by aucubin. This paper provides the scientific basis for Traditional Chinese medicine treating psoriasis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Regulatory T cell (Treg) impairment is implicated in the pathogenesis of chronic inflammatory diseases, but relatively little is known about the therapeutic potential of Treg restoration. Here we present clinical evidence for the Treg-selective interleukin-2 receptor agonist rezpegaldesleukin (REZPEG) in two randomized, double-blind, placebo-controlled Phase 1b trials in patients with moderate-to-severe atopic dermatitis (AD) (NCT04081350) or chronic plaque psoriasis (PsO) (NCT04119557). Key inclusion criteria for AD included an Eczema Area and Severity Index (EASI) score ≥ 16 and a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) ≥ 3, and for PsO included a Psoriasis Area and Severity Index (PASI) score of ≥ 12 and a static Physician's Global Assessment (sPGA) score of ≥ 3. REZPEG is safe and well-tolerated and demonstrates consistent pharmacokinetics in participants receiving subcutaneous doses of 10 to 12 µg/kg or 24 µg/kg once every 2 weeks for 12 weeks, meeting the primary and secondary objectives, respectively. AD patients receiving the higher dose demonstrate an 83% improvement in EASI score after 12 weeks of treatment. EASI improvement of ≥ 75% (EASI-75) and vIGA-AD responses are maintained for 36 weeks after treatment discontinuation in 71% and 80% of week 12 responders, respectively. These exploratory clinical improvements are accompanied by sustained increases in CD25 bright Tregs. REZPEG thus represents a homeostatic approach to cutaneous disease therapy and holds clinical potential in providing long-term, treatment-free disease control., (© 2024. The Author(s).)

Background: Psoriasis is a chronic inflammatory skin disease. A strong association between the AhR/ NFκB axis and the inflammatory response in psoriasis. Indigo (IDG) has demonstrated significant anti-inflammatory properties. This study aimed to assess the anti-psoriatic efficacy of IDG while investigating the underlying mechanisms involved., Methods: In the in vitro experiments, cell viability was assessed using the CCK-8. qRT-PCR was employed to measure the mRNA levels of NF-κB, TNF-α, IL-1β, AhR, and CYP1A1. Western blotting was conducted to examine alterations in cytoplasmic and nuclear AhR protein levels. Additionally, an IDG nanoemulsion (NE) cream was prepared for the in vivo experiments. A psoriasis-like skin lesion mice model was induced using IMQ (62.5 mg/day for 7 days). The severity of psoriasis was evaluated using PASI, and skin lesions were scored while epidermal thickness was assessed via HE staining. The expression of inflammatory markers, including IL-6, IL-13, IL-17A, MCP-1, and TNF-α, was detected in skin lesions using Luminex. The levels of CYP1A1, p65, and p-p65 proteins were determined by Western blotting., Results: LPS stimulation significantly elevated TNF-α, IL-6, and NF-κB mRNA levels, which were notably reduced by IDG treatment. Additionally, IDG significantly enhanced the expression of AhR and CYP1A1 mRNA. Further investigation revealed that IDG facilitated AhR translocation from the cytoplasm to the nucleus. In the IMQ-induced psoriasis-like mouse model, IDG NE substantially ameliorated the severity of skin lesions. Moreover, IDG NE treatment reduced the upregulation of inflammatory cytokines such as IL-6, IL-17A, MCP-1, and TNF-α in IMQ-induced skin lesions. It was also observed that IDG NE treatment increased CYP1A1 protein expression while inhibiting p65 and p-p65 protein expression., Conclusion: IDG emerges as a promising treatment for psoriasis, demonstrating effective therapeutic outcomes. Its mechanism of action is likely linked to the modulation of the AhR/NFκB signaling pathway., Competing Interests: The authors declare that they have no competing interests., (© 2024 Lin et al.)

Localized delivery of inflammasome inhibitors in phagocytic macrophages could be promising for psoriasis treatment. The present work demonstrates the development of non-spherical lipid nanoparticles, mimicking pathogen-like shapes, consisting of an anti-inflammatory inflammasome inhibiting lipid (pyridoxine dipalmitate) as a trojan horse. The nanorods inhibit inflammasome by 3.8- and 4.5-fold compared with nanoellipses and nanospheres, respectively. Nanorods reduce apoptosis-associated speck-like protein and lysosomal rupture, restrain calcium influx, and mitochondrial reactive oxygen species. Dual inflammasome inhibitor (NLRP3/AIM-2-IN-3) loaded nanorods cause synergistic inhibition by 21.5- and 59-folds compared with nanorods and free drug, respectively alongside caspase-1 inhibition. The NLRP3/AIM-2-IN-3 nanorod when transformed into a polymeric scaffold, simultaneously and effectively inhibits RNA levels of NLRP3, AIM2, caspase-1, chemokine ligand-2, gasdermin-D, interleukin-1β, toll-like receptor 7/ 8, and IL-17A by 6.4-, 1.6-, 2.0-, 13.0-, 4.2-, 24.4-, 4.3-, and 1.82-fold, respectively in psoriatic skin in comparison to Imiquimod positive control group in an in-vivo psoriasis-like mice model., (© 2024. The Author(s).)

A literature search on the subject of botulinum toxin treatment in psoriasis found 15 relevant articles, 11 on human subjects and 4 on animal studies. Of the human data, eight were clinical trials and three were single case reports. Seven out of eight clinical trials, all open-label, reported improvement in psoriasis following intradermal or subcutaneous botulinum toxin injections. One double-blind, placebo-controlled study, which used a smaller dose than the open-label studies, did not note a healing effect. Animal studies have shown that injection of botulinum toxins in the skin heals psoriatic skin lesions and can reduce the level of interleukins (ILs) and cytokines as well as inflammatory cells in psoriatic plaques. There is a need for controlled, blinded studies conducted in larger numbers of patients with doses that have shown promise in open-label studies.

Introduction: Generalized pustular psoriasis (GPP) is a rare and potentially life-threatening auto-inflammatory disease. Currently, there are no consensus-based guidelines or universally accepted treatments. Biologics represent a potential therapeutic option. This study systematically assessed the efficacy and safety of biologics in GPP., Methods: Relevant studies from three databases were systematically searched until June 28, 2024. Statistical information, including the single-arm proportion rate of the outcomes and 95% confidence intervals (CIs), was analyzed to determine treatment effects. Heterogeneity was assessed using I² values, and subgroup analyses were performed based on drug targets and treatment durations. Data were quantitatively synthesized using a random-effects meta-analysis. Analyses were performed using R statistical software version 4.4.0., Results: A total of 329 patients from 16 studies were included. The proportion of responders treated with IL-36 inhibitors and IL-17 inhibitors is higher than those treated with TNF-α inhibitors and IL-23 inhibitors. IL-36 inhibitors appear to achieve the highest response rates between 4 and 8 weeks, while IL-17 inhibitors, TNF-alpha inhibitors, and IL-23 inhibitors show a gradual increase in response rates up to 12 weeks. IL-36 inhibitors achieve a 40% (95% CI: 27%-54%) GPPASI75 response rate and a 55% (95% CI: 41%-68%) GPPGA (0,1) response rate within 2 weeks, significantly outperforming other biologics. The recurrence rates of GPP within 52 weeks, ranked from highest to lowest, are: IL-36 inhibitors (21% [95% CI: 9%-28%]), TNF-alpha inhibitors (20% [95% CI: 2%-46%]), IL-17 inhibitors (15% [95% CI: 1%-37%]), and IL-23 inhibitors (5% [95% CI: 0%-29%]). Additionally, 6% (95% CI: 1%-11%) of patients experienced severe adverse events., Discussion: This meta-analysis highlights the efficacy and safety of biologics in patients with GPP, offering valuable evidence to guide future clinical practice. IL-36 inhibitors show a faster and more substantial clinical response in GPP compared to other biologics. Further research is necessary to assess their role in specific subpopulations and to evaluate their potential long-term effects on flare prevention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Liu, Dong and Bai.)

Psoriasis is a chronic inflammatory skin disorder with multiple causes, including genetic and environmental factors. Despite advances in treatment, there remains a need to identify novel therapeutic targets. A Mendelian randomization (MR) analysis was conducted to identify therapeutic targets for psoriasis. Data on cis-expression quantitative trait loci were obtained from the eQTLGen Consortium (n = 31,684). Summary statistics for psoriasis (outcome) were sourced from the GWAS Catalog with a sample size of 484,598, including 5,427 cases and 479,171 controls. Colocalization analysis was used to assess whether psoriasis risk and gene expression were driven by shared single nucleotide polymorphisms. Drug prediction and molecular docking were utilized to validate the pharmacological value of the drug targets. The MR analysis found that 81 drug targets were significantly associated, and two (TYK2 and PRSS36) were supported by colocalization analysis (PP.H4 > 0.80). Phenome-wide association studies did not show any associations with other traits at the gene level. Biologically, these genes were closely related to immune function. Molecular docking revealed strong binding with drugs and proteins, as supported by available structural data. This study validated TYK2 as a drug target for psoriasis, in line with its existing clinical use, including the development of decucravacitinib. PRSS36 is a potential novel target requiring further investigation., (© 2024. The Author(s).)

The purpose of the current work was to develop and characterize ethosomes of vitamin D3 gel that could more effectively work against psoriasis. Psoriasis is a chronic immune-mediated inflammatory skin disease. Due to vitamin D3 role in proliferation and maturation of keratinocytes, it has become an important local therapeutic option in the treatment of psoriasis. In this research we have initiated worked on ethosomes gels containing vitamin D3 to treat psoriasis. Soya lecithin 1-8% (w/v), propylene glycol and ethanol were used to create the formulations, which were then tested for vesicle size, shape, surface morphology, entrapment effectiveness, and in vitro drug permeation. The drug encapsulation efficiency of ethosomes was 96.25% ± 0.3. The particle sizes of the optimized ethosomes was 148 and 657 nm, and the PDI value was 0.770 ± 0.12 along with negative charge - 14 ± 3. Fourier transform infrared (FT-IR) spectroscopy and differential scanning calorimetry (DSC) along with thermogravimetric analysis (TGA) studies confirmed the absence of interactions between vitamin D3 and other ingredients. It was determined that the total amount of medication that penetrated the membrane was 95.34% ± 3. Percentage lysis was very negligible for all strengths which were found less than 15%. Based on our research, ethosomes appear to be safe for use. The vitamin D3 ethosomal gel order, description, pH, and viscosity were all within the specified ranges, according to the findings of a 6-month investigation into the stability profile of the completed system. In this research, we successfully prepared ethosomes loaded with vitamin D3 and then converted it into gel for patients' easy applications., (© 2024. The Author(s).)

Introduction: Concentrated Growth Factor (CGF), rich in CD34 + stem cells, is widely used in treatments for androgenetic alopecia and skin rejuvenation due to its immune-modulating properties. Psoriasis, a chronic inflammatory skin condition, presents significant treatment challenges, particularly for patients who cannot use biologics due to conditions such as cancer and lesions resistant to treatments. The potential of CGF in treating psoriasis is promising, given its broad immunoregulatory effects which confirmed in our previous androgenetic alopecia work., Methods: We evaluated the impact of CGF on IL-17 levels in two contexts: patients treated for androgenetic alopecia and a psoriasis mouse model. Twelve patients received three monthly injections of CGF, with serum IL-17 levels measured before and after treatment. In the psoriasis mouse model, groups were treated with CGF, and outcomes were assessed using the Psoriasis Area and Severity Index (PASI), skin barrier scores, histological analysis, and RNA sequencing. Additionally, in vitro experiments applied CD34 + cells from CGF to keratinocytes to measure levels of TNF-α, IFN-γ, IL-23, and IL-17., Results: In patients with androgenetic alopecia, three monthly CGF injections resulted in significantly reduced serum IL-17 levels. In the psoriatic mouse model, CGF-treated groups exhibited lower PASI scores and improved skin barrier scores compared to controls. Histological analysis revealed enhanced skin characteristics, while RNA sequencing demonstrated downregulated IL-17 and upregulated CD34 expression, as well as improved expression of barrier-related genes. In vitro, the application of CD34 + cells from CGF to keratinocytes led to a significant reduction in TNF-α, IFN-γ, IL-23, and IL-17 levels, indicating strong anti-inflammatory effects. A clinical case of a psoriasis patient unresponsive to IL-23 therapy (Guselkumab) showed significant improvement following CGF treatment., Conclusion: These findings indicate that CGF could serve as an effective and versatile treatment for psoriasis, especially for patients who have already undergone biologic therapies but continue to experience resistant lesions., (© 2024. The Author(s).)

The endogenous immunomodulator adenosine (ADO) was expected to be potentialized as an efficacious mediator to combat psoriasis. However, its efficacy is severely hindered by its poor metabolic stability and insufficient accumulation at the dermatological lesions. Methods: In this study, a biomineralized in situ catalytic nanoreactor was delicately customized by encapsulating ADO precursor (adenosine monophosphate, AMP) within the internal porous skeleton of zeolitic imidazolate framework-90, followed by the biomineralization of the AMP catabolic enzyme on the outer layer. The nanocrystals were then incorporated into a dissolving microneedles patch, which was designed to deliver drugs with precision into the cutaneous lesion and enhance the efficacy of psoriasis treatment. Results: Upon penetration into the skin, the nanoreactors were released and underwent a gradual collapse of their structure, releasing AMP when exposed to the acidic microenvironment. Meanwhile, the acidic pH could trigger an in situ catalytic reaction to continuously produce ADO. This system yielded remarkable results in a psoriasis-like mouse model. The mechanism study demonstrated that this system could substantially reshape the inflammatory ecosystem by inhibiting the keratinocyte hyperplasia, reducing inflammatory cytokine expression, and regulating the infiltration of immune cells. Conclusion: The in situ catalytic nanoreactor integrated microneedle patch is a promising modular platform for co-delivery of prodrugs and their catabolic enzymes, offering a potential solution for various diseases., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Recent studies have shown that local injection of secukinumab can achieve positive therapeutic effects when applied in the treatment of nail psoriasis. At present, there have been no other studies on the use of biological agents in the treatment of pediatric nail psoriasis. Three children were included in the study to evaluate the efficacy and safety of periungual injection and long-term injection of secukinumab in the treatment of nail psoriasis in children. It was found that local injection did not achieve a remarkable therapeutic effect. The nail lesions were improved continuously by subcutaneous injection once a month., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Sun, Xie, Liu and Liu.)

Vitamin D plays an important role in psoriasis, but its involvement in pathogenesis remains unclear. This study aimed to evaluate vitamin D receptor (VDR) expression on peripheral blood mononuclear cells (PBMCs) in patients with psoriasis and healthy controls and to study the effects of the Etanercept treatment on VDR expression on PBMCs in patients with psoriasis. Twenty patients with moderate to severe psoriasis received treatment with Etanercept for 24 weeks. The age- and sex-matched controls did not receive any intervention. VDR expression on CD3 + lymphocytes and CD14 + monocytes, and serum levels of total and free 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxy vitamin D (1,25(OH) 2 D) were analyzed at baseline, after 10-12 weeks, and after 24 weeks in both groups. VDR expression was analyzed using flow cytometry. We observed higher expression of the VDR on CD14 + monocytes in psoriasis patients compared to healthy controls at baseline. This difference was no longer significant after 24 weeks of the Etanercept treatment. The patients with psoriasis improved clinically. However, VDR expression was unaltered during the Etanercept treatment, and there was no correlation between VDR expression and disease severity.

Introduction: Endothelial dysfunction is an early precursor of atherosclerosis and is common in patients with psoriasis, presumably primarily due to psoriasis-related inflammation. We investigated endothelial function, arterial stiffness, and circulating markers of endothelial activation in young patients with psoriasis vulgaris of varying severity, all of whom were effectively treated achieving PASI 90., Methods: We conducted a cross-sectional study of 80 patients (54 men/26 women, 30-45 years) who were effectively treated with topical therapy, methotrexate, adalimumab, secukinumab or guselkumab, and 20 healthy controls. Endothelial dysfunction was measured by flow-mediated dilation and arterial stiffness was measured by pulse wave velocity and common carotid artery stiffness. The following circulating biomarkers of endothelial activation were measured: ICAM-1, VCAM-1, E- and P-selectin, GDF-15, and TRAIL., Results: Endothelial function and arterial stiffness parameters did not differ between patients with effectively treated psoriasis and the control group. Circulating endothelial activation biomarkers did not show relevant differences between the groups of effectively treated patients or controls., Discussion: Although cardiovascular disease is the leading cause of morbidity and mortality in patients with psoriasis, effective antipsoriatic treatment appears to slow the progression of atherosclerosis, even when there are cardiovascular risk factors, such as smoking or obesity. This may suggest that antipsoriatic treatment exerts a cardioprotective effect., Conclusions: Our results suggest that early and effective treatment of varying-severity psoriasis vulgaris in young patients appears to prevent arterial dysfunction related to psoriasis and consequent cardiovascular risk.The study is registered at http://clinicaltrials.gov (identifier: NCT05957120)., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: Cold plasma has shown efficacy in various dermatological applications by reduces inflammatory responses and modulating cytokine expression. Therefore, this study aimed to investigate the therapeutic effects of cold plasma on psoriasis., Methods: In psoriasis HaCaT cells with cold plasma, we confirmed the expression of inflammatory cytokines involved in psoriasis formation and MAPK pathway, cell cycle, and apoptosis-related factors. In psoriasis-like BALB/c mice model, the effects of cold plasma treatment on skin were visually assessed. The expression of psoriasis-related factors was confirmed through qPCR, Western blotting, and Immunohistochemistry., Results: Cold plasma led to a reduction in inflammatory cytokines including IL-17A, IL-23A, IL-24, IL-1β, and TNF-α in the psoriasis cell line. It also modulated factors involved in the MAPK pathway and the cell cycle. In the psoriasis-like mice model, cold plasma resulted in improvements in skin thickness, erythema, scaling, and PASI. Additionally, decreases in inflammatory cytokines like INF-γ, IL-23, and S100a7 were observed, along with improvements in MAPK pathway activation, apoptosis, and other psoriasis-related factors., Conclusion: Through in vitro and in vivo studies, our research highlights the potential of cold plasma as a novel therapeutic approach for psoriasis. Furthermore, cold plasma could serve as an adjunctive treatment for skin immunological diseases., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Psoriasis is a chronic condition caused by an inflammation mediated mainly by cytokines and T cells. In COVID-19, the same type of imbalance is common, generating the Cytokine Storm and promoting a worsening in the skin conditions of patients with autoimmune disorders, such as Psoriasis. In this context, one of the main mediators of immune responses presented by SARS-CoV-2 infected patients is the Purinergic System. This immunological resource is capable of stimulating the hyperinflammatory state presented by infected individuals, mainly by the activity of the P2X7 receptor, culminating in the Cytokine Storm and consequently in the Psoriasis crisis. Currently, different drugs are used for patients with Psoriasis, such as immunosuppressants and small molecules; however, the safety of these drugs in infected patients has not been analyzed yet. In this context, studies are being developed to evaluate the possible administration of these traditional drugs to COVID-19 patients with Psoriasis crisis. Along with that, researchers must evaluate the potential of administrating P2X7 antagonists to these patients as well, improving both the systemic and the dermatological prognostics of patients, by reducing the Cytokine Storm and its general effects, but also avoiding the provocation of Psoriasis crisis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The pathogenesis of psoriasis involves the interaction between keratinocytes and immune cells, leading to immune imbalance. While most current clinical treatment regimens offer rapid symptom relief, they often come with significant side effects. Tetrastigma hemsleyanum polysaccharides (THP), which are naturally nontoxic, possess remarkable immunomodulatory and anti-inflammatory properties., Methods: In this study, we utilized an imiquimod (IMQ)-induced psoriasis mouse model and a LPS/IL-6-stimulated HaCaT model. The potential and mechanism of action of THP in psoriasis treatment were assessed through methods including Psoriasis Area Severity Index (PASI) scoring, histopathology, flow cytometry, immunoblotting, and reverse transcription-polymerase chain reaction (RT-PCR)., Results: Percutaneous administration of THP significantly alleviated symptoms and manifestations in IMQ-induced psoriatic mice, including improvements in psoriatic skin appearance (erythema, folds, scales), histopathological changes, decreased PASI scores, and spleen index. Additionally, THP suppressed abnormal proliferation of Th17 cells and excessive proliferation and inflammation of keratinocytes. Furthermore, THP exhibited the ability to regulate the JAK/STAT3 signaling pathway., Conclusion: Findings from in vivo and in vitro studies suggest that THP can inhibit abnormal cell proliferation and excessive inflammation in lesional skin, balance Th17 immune cells, and disrupt the interaction between keratinocytes and Th17 cells. This mechanism of action may involve the modulation of the JAK/STAT3 signaling pathway, offering potential implications for psoriasis treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

It is often a goal of model development to predict data from which a variety of outcomes can be derived, such as threshold-based categorization or change from baseline (CFB) transformations. This approach can improve power or support multiple decisions. Because these derivations are indirectly predicted from the model, they are valuable tests for misspecification when used in visual or numeric predictive checks (V/NPCs). However, derived outcome V/NPCs (especially if primary or key secondary) are often overly scrutinized and held to an uncommon standard when comparing model predictions to point estimates, even if by conventional standards both the directly and indirectly modeled data are captured well. Here, simulations of directly modeled data were used to determine where apparent issues in V/NPCs of derived outcomes are expected. Two types of datasets were simulated: (1) a simple pre-post study and (2) pharmacokinetic/pharmacodynamic data from a dose-ranging study. A psoriasis exposure-response model case study was also assessed. V/NPCs were generated on the raw data, CFB data, and placebo-corrected CFB (dCFB) data, and binned summary statistics of the observed data for each trial were graded as being strongly or weakly supportive of a predictive model (within the interquartile range or the 95% central distribution of all simulated trials, respectively). In all cases, the strength of support in direct data V/NPCs was minimally related to that in derived outcome V/NPCs. There are myriad benefits to modeling the underlying data of a derived measure, and these results support caution in discarding adequate models based on overly strict derived measure predictive checks., (© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Immune-mediated inflammatory diseases (IMIDs) comprise a broad spectrum of conditions characterized by systemic inflammation affecting various organs and tissues, for which there is no known cure. The isoform-specific inhibition of phosphodiesterase-4B (PDE4B) over PDE4D constitutes an effective therapeutic strategy for the treatment of IMIDs that minimizes the adverse effects associated with non-selective PDE4 inhibitors. Thus, we report a new class of isoquinolone derivatives as next-generation PDE4 inhibitors for effective management of rheumatoid arthritis (RA) and psoriasis. Among the series, 8 compounds i.e. 1e, 1l, 1m, 1n, 1o, 2m, 2o and 3o showed promising PDE4B inhibition (>80 %) in vitro with IC 50  ∼ 1.4-6.2 µM. The compound 1l was identified as an initial hit and was pursued for further studies. According to structure-activity relationship (SAR), an allyl group at C-4 position improved PDE4B inhibition. The correlation between in vitro activity data and binding affinities obtained via molecular docking suggested that the high-affinity binding to PDE4B is a prerequisite for the effective inhibition of PDE4B. Notably, the hit 1l showed selectivity towards PDE4B over PDE4D in vitro. Furthermore, 1l treatment (30 mg/kg) in the adjuvant-induced arthritis (AIA) rat model induced by complete Freund's adjuvant (CFA) demonstrated anti-arthritic potential via ameliorating paw swelling and body weight, narrowing joint space, reducing excessive immune cells infiltration and pannus formation in addition to reducing mRNA expression of pro-inflammatory cytokines such as TNF-α and IL-6 in synovial tissues of experimental rats. Additionally, 1l reduced the hyper-proliferative state and colony forming potential of IMQ-induced psoriatic keratinocytes. The treatment of these cells with 1l markedly reduced the protein levels of Ki67 and mRNA levels of pro-inflammatory cytokines e.g. IL-17A and TNF-α suggesting its potent anti-psoriatic potential. Furthermore, 1l did not show any significant adverse effects when evaluated in a systematic toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity) studies in zebrafish at the tested concentrations (1-100 µM) and the NOAEL (no-observed-adverse-effect level) was found to be 100 µM. Thus, with promising anti-inflammatory effects both in vitro and in vivo along with PDE4B selectivity with an acceptable safety margin, 1l emerged as a new and promising inhibitor for further studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Spanish Autonomous Communities (ACs) are entitled to decide on the prescription requirements of their own territories, which can create inequalities in access to new drugs in the management of psoriasis. The objective of this study was to assess whether the level of restrictions in the access to new drugs for the management psoriasis was associated with the probability of achieving disease control measured using the Minimum Disease Activity (MDA) criteria. Therefore, we combined the results of 2 previous independent, cross-sectional studies: one that described the MDA in psoriasis by AC, and another that evaluated the level of restrictions to drug access by AC. We found that the higher the number of restrictions the lower the chances of achieving the MDA criteria (P=.013). Our results suggest that, in Spain, geographical differences in the access to new drugs may be creating health inequalities across the country., (Copyright © 2024 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Psoriasis is a troublesome scaling skin disease with no high-effective medication available by far. Signal transducer and activator of transcription 3 (STAT3) has recently been revealed as a crucial player in the pathogenesis and progression of psoriasis and emerged as an intriguing antipsoriatic drug target. Naturally occurring lapachol and its quinone analogs had been discovered as effective STAT3 inhibitors, however, their antipsoriatic effects are not well investigated. Previously, we have reported a series of isothiazoloquinone lapachol derivatives. Here, the antipsoriastic potentials of these isothiazoloquinones were investigated and, in addition, 35 novel isoxazoloquinone derivatives were prepared and studied for their anti-psoriasis properties. Among them, the most potent antipsoriatic compound B20 determined by in vitro test on HaCaT cells could directly bind to STAT3, reduce STAT3 level and inhibit STAT3 nuclear translocation. In vivo studies showed that topical application of B20 could effectively alleviate IMQ-induced psoriasis in mice with no obvious side effects. In addition, B20 inhibited the production of interleukin 17 (IL-17A), a STAT3-downstream cytokine essential for the progression of psoriasis, both in vitro and in vivo. Thus, isoxazoloquinone B20 is a potent STAT3-targeting antipsoriatic agent worth of further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Spanish Autonomous Communities (ACs) are entitled to decide on the prescription requirements of their own territories, which can create inequalities in access to new drugs in the management of psoriasis. The objective of this study was to assess whether the level of restrictions in the access to new drugs for the management psoriasis was associated with the probability of achieving disease control measured using the Minimum Disease Activity (MDA) criteria. Therefore, we combined the results of 2 previous independent, cross-sectional studies: one that described the MDA in psoriasis by AC, and another that evaluated the level of restrictions to drug access by AC. We found that the higher the number of restrictions the lower the chances of achieving the MDA criteria (P=.013). Our results suggest that, in Spain, geographical differences in the access to new drugs may be creating health inequalities across the country., (Copyright © 2024 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Psoriasis is a chronic, relapsing, and refractory immune-mediated skin disease with the etiology and pharmaceutical targets remaining unsatisfactorily addressed. Topical herbal-derived compounds, such as tryptanthrin (Tryp), have been considered as an alternative therapy for psoriasis due to their lower costs and fewer side effects compared to other therapies. However, the effectiveness of topically administered drugs is substantially limited by the thickened pathological skin barrier and the low bioavailability of drugs in the deeper layers of the lesion. Ethosomes, being a novel phospholipid-based vesicle system with high content of ethanol, have been implicated in enhancing topical drug absorption and restoring psoriatic lesions. In this study, taking advantages of ethosomes as a soft and malleable drug carrier, we constructed the Tryp-loaded ethosome (Tryp-ES) through a one-step microfluidics-based technique. The optimal formulation of Tryp-ES was achieved by adding amino-acid-derived surfactant sodium lauroyl glutamate, and Tryp-ES exhibited homogeneous particle size and favorable stability at room temperature. In vitro evaluations showed that Tryp of Tryp-ES could be easily internalized into cells and accumulated in cell nuclei, hence inhibited the abnormally proliferated keratinocytes by inducing apoptosis. In vivo and in vitro assessment using psoritic skin of mice revealed that Tryp-ES had preferred skin retention and permeation of loaded drugs within the initial 1 h of topical administration, which could be attributed to transient disintegrations of cell membranes by ethosomes, thus improved cellular fluidity and permeability. Notably, a synergistic effect of ethosomes and Tryp was found in psoriatic mice. Tryp-ES-treated mice showed substantially ameliorated symptoms of psoriasis and reduced pathological alterations due to hyperplasia, inflammation and angiogenesis, without detectable local or systemic toxicities. Interestingly, lipidomics analysis confirmed that the supplementation of phospholipids, as in the form of ethosome vehicles, was an alterantive strategy to relieve psoriatic pathologies. Taken together, this study provides a novel impact for ethosomal topical delivery of Tryp and underlines their potential as an effective therapy for the management of psoriasis., (© 2024. The Author(s).)

Psoriasis is a complex inflammatory skin disease manifested by altered proliferation and differentiation of keratinocytes with dysfunctional apoptosis. This study aimed to identify regulatory factors and comprehend the underlying mechanisms of inefficient apoptosis to open up promising therapeutic approaches. Incorporating human protein interactions, apoptosis proteins, and physical relationships of psoriasis-apoptosis proteins helped us to generate a psoriasis-apoptosis interaction (SAI) network. Subsequently, topological and functional analyses of the SAI network revealed effective proteins, functional modules, hub motifs, dysregulated pathways and transcriptional gene regulatory factors. Network pharmacology, molecular docking and molecular dynamics simulation methods identified the potential drug-target interactions. RELA, MAPK1, MAPK3, MMP9, IL1B, AKT1 and STAT1 were revealed as effective proteins. The MAPK1-MAPK3-RELA motif was identified as a hub regulator in the crosstalk between 41 pathways. Among all pathways, "lipid and atherosclerosis" was found to be the predominant pathway. Acetylcysteine, arsenic-trioxide, β-elemene, bortezomib and curcumin were identified as potential drugs to inhibit pathway crosstalk. Experimental verifications were performed using the literature search, GSE13355 and GSE14905 microarray datasets. Drug-protein-pathway interactions associated with apoptosis were deciphered. These findings highlight the role of hub motif-mediated pathway-pathway crosstalk associated with apoptosis in the complexity of psoriasis and suggest crosstalk inhibition as an effective therapeutic approach., (© 2024. The Author(s).)

The gut microbiota plays a critical role in immune system function, with dysbiosis linked to systemic inflammation, contributing to conditions like psoriasis and depression. Although biological treatments for severe psoriasis are known to impact gut bacteria, less is understood about their effects on fungi. This study aims to investigate fungal gut microbiota changes in psoriasis patients transitioning from TNF-α inhibitors to brodalumab. Fecal samples from 20 patients were analyzed using Illumina MiSeq sequencing of the ITS2 region of 18S rRNA. Microbial diversity was assessed through Bray-Curtis dissimilarity and the Shannon-Wiener index. Clinical outcomes were measured using clinical scores for psoriasis and depression severity, with statistical analysis performed via Wilcoxon signed-rank tests and PERMANOVA. Results showed that Ascomycota was the dominant fungal phylum in both treatment groups, with Saccharomyces , Penicillium , Candida , and Debaryomyces as prevalent genera. No significant changes occurred at the phylum level after switching to brodalumab, though minor genome-level variations were observed. Beta diversity analysis highlighted inter-patient variability, with no significant correlation between fungal composition and clinical outcomes. Despite improved clinical scores, the fungal gut microbiota remained largely stable, suggesting that brodalumab does not significantly alter fungal communities in psoriasis patients. Further research is needed for a comprehensive understanding.

Psoriasis is a chronic, non-contagious, immune-mediated skin disorder. Inflammation of the skin's surface is characterised by scaly white, red, or silvery spots that occur due to the hyper-proliferation of keratinocytes in the epidermal layer. Primarily, pharmaceutical drugs or immune therapy are used to treat psoriasis. We are all aware that, certain therapeutic strategies can have some adverse effects, and over time, that hidden inflammation may manifest. This article introduces a mathematical model for psoriasis, formulated by employing a set of nonlinear ordinary differential equations (ODEs) that describe the densities of T-cells, dendritic cells (DCs), keratinocytes, and mesenchymal stromal cells (MSCs) as basic cell populations. A tumor necrosis factor- α ( T N F - α ) inhibitor has been imposed from the initial stage of the treatment regime, using the optimal control theoretic approach, and the numerical results have been observed. After 80 days of monitoring using only biologic T N F - α inhibitors, if this approach did not provide the intended outcomes (when severity arises), stem cells are administered a few times in a pulsed manner as a cell replacement technique in addition to this anti T N F - α medicine. We have observed the combined therapeutic benefit of stem cell replacement with a T N F - α inhibitor from a mathematical point of view. The theoretical analysis and the numerical results revealed that stem cell transplantation, along with a T N F - α inhibitor, is a promising psoriasis treatment option moving forward., (© 2024. The Author(s).)

Objective: In Malaysia, there is now a dearth of recommendations pertaining to the priority of biologic treatments for the effective management of psoriasis, given the multitude of available therapeutic alternatives. Present analysis reports results of a cost-effectiveness model that determines the most optimal arrangement of biologic treatments, with a particular focus of adding biosimilars to the existing treatment pathway for psoriasis in Malaysia., Methods: A Markov model was developed to compare the cost effectiveness of various biologic sequential treatments in a hypothetical cohort of moderate to severe psoriasis patient in Malaysia over a lifetime horizon. The model simulated the progression of patients through three lines of active biologic therapy, before transitioning to best supportive care. Costs and effects were discounted annually at a rate of 3%., Results: First line secukinumab has produced lowest incremental cost effectiveness ratios (ICERs) when compared to first line systemic [ICERs value; US$152,474 (first set analysis) and US$110,572 (second set analysis)] and first line phototherapy [ICERs value; US$147,057 (first set analysis) and US$107,616 (second set analysis)]. However, these values were slightly higher than the Malaysian based threshold of three times gross domestic product per capita, US$104,337. A 40% reduction in the unit costs of reference biologics renders most of the evaluated treatment sequences cost-effective., Conclusion: Adding biosimilar to the current treatment sequence could achieve cost savings ranging from 4.3% to 10.8% without significant loss of effectiveness. Given the significant impact of comorbidities and the resulting decline in quality of life among individuals with psoriasis, it may be justifiable to establish a threshold of up to US$184,000 per quality-adjusted life year (QALY) for the provision of therapies in the context of Malaysia., Competing Interests: The authors have no competing interests to declare that are relevant to the content of this article., (Copyright: © 2024 Azizam et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Despite the abundance of data concerning biologic treatments for patients with psoriasis, clinicians are often challenged with discerning the optimal treatment for each patient. To inform this selection, this study explored whether a patient's baseline characteristics or disease profile could predict the likelihood of achieving complete skin clearance with biologic treatment. Machine-learning and other statistical methods were applied to the substantial data collected from patients with moderate-to-severe psoriasis in the ongoing, international, prospective, observational Psoriasis Study of Health Outcomes (PSoHO). The 3 measures of complete skin clearance were a psoriasis area and severity index (PASI)100 response at (a) week 12, (b) month 12, and (c) week 12 and maintain ed at month 6 and month 12 (PASI100 durability). From these real-world data, the absence of nail psoriasis emerged  as the most consistent feature that may be used by clinicians to predict high-level treatment responses with biologic treatment. Other significant predictors of skin clearance with biologic treatments were the absence of hypertension and a lower body surface area affected by psoriasis. Overall, this study evidences the substantial challenge of identifying reliable clinical markers of treatment response for patients with psoriasis and highlights the importance of regular screening for psoriatic nail involvement.

Mild psoriasis may be burdensome; if symptoms are inadequately controlled, switching therapy may be warranted. In the Phase 3 NAVIGATE trial, patients with moderate-to-severe plaque psoriasis received ustekinumab for 16 weeks. Patients with inadequate response (Investigator's Global Assessment [IGA] ≥ 2) were randomized to switch to guselkumab or continue ustekinumab. This post-hoc analysis evaluated the patient subgroup with residual mild psoriasis (IGA = 2) after initial ustekinumab therapy. Outcomes assessed included the Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI), and Psoriasis Symptoms and Signs Diary (PSSD). Initially, 871 patients received ustekinumab. At Week 16, 161 randomized patients had residual mild psoriasis (IGA = 2). Among guselkumab- vs ustekinumab-treated patients at Week 28, 59.0% vs 27.7% achieved PASI 90, and 50.0% vs 21.0% achieved DLQI 0/1. Mean changes from baseline in PSSD score were -44 vs -28 and -50 vs -32, respectively, with thresholds of -40 considered clinically meaningful. Mean changes in PSSD itch score were -4.6 vs -2.9, with reductions ≥ 4.0 considered clinically meaningful. Treatment differences were maintained/increased through Week 52. Among patients with residual mild psoriasis after 16 weeks of ustekinumab, those switching to guselkumab had greater improvements in skin clearance, health-related quality of life, and patient-reported symptoms and signs than those continuing ustekinumab.

The plasma membrane protein caveolin-1 (CAV-1) regulates signaling by inhibiting a wide range of kinases and other enzymes. Our previous study demonstrated that the downregulation of CAV-1 in psoriatic epidermal cells contributes to inflammation by enhancing JAK/STAT signaling, cell proliferation, and chemokine production. Administration of the CAV-1 scaffolding domain (CSD) peptide suppressed imiquimod (IMQ)-induced psoriasis-like dermatitis. To identify an optimal therapeutic peptide derived from CAV-1, we have compared the efficacy of CSD and subregions of CSD that have been modified to make them water soluble. We refer to these modified peptides as sCSD, sA, sB, and sC. In IMQ-induced psoriasis-like dermatitis, while all four peptides showed major beneficial effects, sB caused the most significant improvements of skin phenotype and number of infiltrating cells, comparable or superior to the effects of sCSD. Phosphorylation of STAT3 was also inhibited by sB. Furthermore, sB suppressed angiogenesis both in vivo in the dermis of IMQ-induced psoriasis mice and in vitro by blocking the ability of conditioned media derived from CAV-1-silenced keratinocytes to inhibit tube formation by HUVEC. In conclusion, sB had similar or greater beneficial effects than sCSD not only by cytokine suppression but by angiogenesis inhibition adding to its ability to target psoriatic inflammation., (© 2024. The Author(s).)

The primary pathological features of psoriasis include excessive epidermal keratinocytes and infiltration of inflammatory cells, which are pivotal targets for psoriasis therapy. Astragaloside IV (AS-IV), the principal active compound of astragalus, exhibits anti-inflammatory, antioxidant, and immune-modulatory properties. This study aims to investigate AS-IV's anti--psoriatic effects and underlying mechanisms. Normal human epidermal keratinocytes (NHEKs) were stimulated with a combination of TNF-α, IL-17A, IL-1α, IL-22, and oncostatin M (M5) to replicate psoriatic keratinocyte pathology in vitro . Cell proliferation was assessed using CCK8 and EDU staining. Pro-inflammatory cytokine levels were measured via qRT-PCR. In addition, an imiquimod (IMQ)-induced psoriasis mouse model was utilized. Skin histology changes were evaluated with HE staining, while IL-6 and TNF-α levels in mouse serum were quantified using ELISA. NF-κB pathway protein expression was analyzed by western blotting. The results demonstrated that AS-IV inhibited M5-induced proliferation of NHEKs. AS-IV reduced M5-stimulated IL-1β, IL-6, IL-8, TNF-α, IL-23, and MCP-1 expression in NHEKs. Moreover, M5-induced phosphorylation of IκBα and p65 was significantly attenuated by AS-IV. Furthermore, AS-IV application ameliorated erythema, scale formation, and epidermal thickening in IMQ-induced psoriasis-like mouse models. AS-IV also decreased IL-6 and TNF-α levels in mouse serum and inhibited IκBα and p65 phosphorylation in skin tissues. However, prostratin treatment reversed these effects. These findings underscore AS-IV's capacity to mitigate M5-induced NHEK proliferation and inflammation. AS-IV shows promise in alleviating IMQ-induced psoriasis-like skin lesions and inflammation by suppressing the NF-κB pathway., Competing Interests: The authors state that there are no conflicts of interest to disclose.

Introduction: Psoriasis is an immune-mediated inflammatory skin disease. First-line topical treatments include steroids, calcineurin inhibitors, vitamin D analogs, and anthralin. Recently, novel topical therapeutics like tapinarof and roflumilast have emerged with unique anti-inflammatory mechanisms and promising efficacy profiles., Materials and Methods: This review utilized PubMed, SCOPUS, and Web of Science databases to identify recent studies on tapinarof and roflumilast. Criteria focused on efficacy, safety profiles, and therapeutic roles in psoriasis treatment., Results: Four primary literature articles were identified for tapinarof and five for roflumilast. Both drugs demonstrated strong efficacy with minimal adverse events in treating mild-to-moderate plaque psoriasis. Tapinarof showed more frequent but mild adverse effects, while roflumilast had less frequent but more severe side effects., Discussion: Tapinarof and roflumilast offer once-daily dosing and successful treatment in restricted areas, potentially enhancing patient adherence. Cost remains a limiting factor, necessitating future comparative studies to evaluate the efficacy, safety, and cost-effectiveness between the two drugs., Conclusion: Tapinarof and roflumilast present promising topical treatments for psoriasis, showing efficacy and manageable safety profiles. Further research is crucial to fully elucidate their comparative benefits and drawbacks in clinical practice., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Psoriasis is a chronic inflammatory disease and is difficult to cure. In this work, a series of novel chrysin derivatives have been designed and prepared while evaluating anti-inflammatory activities in vitro and in vivo. In vitro, RAW264.7 cells were used to detect the inflammatory activities at first, and compounds 4h, 4k, and 4o significantly decreased the levels of NO, TNF-α, and IL-6. In particular, compound 4o showed superior anti-inflammatory activities than other compounds. Moreover, compound 4o decreased the level of IL-17A in LPS-induced HaCaT cells in vitro. The effect and mechanism of anti-inflammatory activities on psoriasis were determined by imiquimod (IMQ)-induced psoriasis-like mice in vivo. Compound 4o deduced the level of IL-6, IL-17A, IL-22, IL-23, and TNF-α, and showed potent anti-psoriasis activity. Further mechanism study suggested that compound 4o could improve the skin inflammation of psoriasis by inhibiting the NF-κB and STAT3 signaling pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Psoriasis is one of the most prevalent and chronic inflammatory disease of the skin, associated with disrupted barrier function. Currently, a widely accepted, generally usable cell culture model has not been developed yet. In the present work, we aimed to establish a co-culture model with human keratinocyte (HaCaT) and human monocyte cells (THP-1) induced by Imiquimod (IMQ), which acts on the TLR7 receptor. The role of TLR7 expressed on THP-1 cells was confirmed by immunofluorescence staining of NF-κB activation. Chloroquine (CH) was used as a receptor inhibitor, in the presence or absence of which the NF-κB pathway was activated. We determined the most effective proliferation-stimulating IMQ concentration by RTCA method and the hyperproliferative effect was investigated by wound-healing test. The effect of IMQ was compared with the effects of the anthocyanin (AC) components from the anti-inflammatory sour cherry extract that we have already studied. We found that IMQ significantly increased the migration rate however, the combined treatment resulted in a decreased migration rate compared to the IMQ treatment alone. Inflammatory cytokines were measured from the supernatant of co-culture by ELISA. During the development of the co-culture intended to model psoriasis, we confirmed the induction effect of IMQ and in the case of AC treatment, we supported the stabilizing effect of the barrier., Competing Interests: Declaration of competing interest We wish to confirm that there is no conflict of interest associated with this publication., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background The paradoxical occurrence of psoriasis triggered by Interleukin-17 (IL-17) inhibitors is notable due to its prominent symptoms and the therapeutic dilemma it presents for follow-up care. Objective To describe cases in our clinic, perform an in-depth literature review, and suggest the most probable mechanisms of action. Method We conducted a literature review on published cases of IL-17 inhibitor-induced psoriasis. Results We found 22 articles reporting 30 cases of IL-17 inhibitor-induced paradoxical psoriasis, primarily observed in patients with a previous psoriasis history. Almost 60% of cases showed a change in lesion morphology, with the plaque or pustular type being prevalent. About 73.3% of patients had to discontinue the implicated drug, leading to partial or complete symptom resolution. The mechanism behind this response seemed to involve IL-17 inhibitors downregulating Tumour Necrosis Factor alpha (TNF-α), subsequently upregulating plasmacytoid dendritic cells and triggering unopposed IFN-alpha (IFN-α) production. Limitation Data are confined to case reports and case series. Conclusion More assertive measures are recommended for treating paradoxical psoriasis induced by IL-17 inhibitors than those caused by TNF-α inhibitors. Reintroducing an IL-17 inhibitor is not advised, as patients did not show improvement.