Positive association between insulin resistance and fatty liver disease in psoriasis: evidence from a cross-sectional study.

Background: Fatty liver disease (FLD) is a common comorbidity of psoriasis and is often referred to as non-alcoholic fatty liver disease (NAFLD). However, the role of inflammation or insulin resistance (IR) in FLD is inconclusive. The study aims to explore whether FLD in psoriasis patients is more related to insulin resistance or systemic inflammation level. Methods: Data for this study were collected from the Shanghai Psoriasis Effectiveness Evaluation Cohort, a prospective cohort that examines psoriasis characteristics in the Chinese population. IR was assessed using the triglyceride glucose (TyG) and TyG-body mass index (TyG-BMI) indicators. Systemic non-specific inflammation was assessed using the neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), and systemic immune inflammation index (SII). Results: The analysis included a total of 647 patients. Subsequent logistic regression analysis revealed that NLR, dNLR, and SII were not significantly associated with FLD in psoriasis patients, while TyG and TyG-BMI showed significant associations with FLD. Subgroup analysis indicated that in the majority of subgroups, TyG and TyG-BMI were significantly associated with FLD, particularly TyG-BMI. Excluding individuals with methotrexate and acitretin resulted in consistent findings with the main analysis. Further analysis revealed a significantly higher diagnosis rate of metabolic-associated fatty liver disease (MAFLD) compared to NAFLD. Conclusions: Metabolic factors play a crucial role in FLD in patients with psoriasis, and TyG and TyG-BMI are potential predictors of FLD. Therefore, MAFLD can be recommend as a term to describe FLD in psoriasis patients. Trial registration: https://www.chictr.org.cn/showproj.html?proj=58256, identifier ChiCTR2000036186. A multi-center clinical study of systemic treatment strategies for psoriasis in Chinese population. Registered 31 August 2020.

Better efficacy, lower recurrence rate and decreased CD8+TRM with guselkumab treatment for generalized pustular psoriasis: A prospective cohort study from China.

Generalized pustular psoriasis (GPP) is a severe and uncommon form of psoriasis, for which treatment options are limited. There is an urgent need to expand the treatment options for GPP. Currently, adalimumab, secukinumab, and guselkumab are considered effective for GPP, but there is a lack of prospective direct comparative studies on their efficacy for GPP. We conducted a prospective, single-center, observational study on 50 GPP patients to compare the efficacy, safety, and recurrence rates of these three biologics. Adalimumab, secukinumab, and guselkumab resulted in varying degrees of improvement in patients with GPP, but guselkumab exhibited superior efficacy and a lower recurrence rate than the other two drugs. This enhanced response may be attributed to the significant reduction in CD8+ tissue-resident memory T cells within GPP lesions caused by guselkumab.

A novel online calculator based on clinical features and hematological parameters to predict total skin clearance in patients with moderate to severe psoriasis.

BACKGROUND: Treatment responses to biologic agents vary between patients with moderate to severe psoriasis; while some patients achieve total skin clearance (TSC), a proportion of patients may only experience partial improvement. OBJECTIVE: This study was designed to identify potential predictors for achieving TSC in psoriasis patients treated with IL-17 inhibitors. It also aimed to develop an easy-to-use calculator incorporating these factors by the nomogram to predict TSC response. METHODS: A total of 381 patients with psoriasis receiving ixekizumab were included in the development cohort and 229 psoriasis patients who initiated secukinumab treatment were included in the validation cohort. The study endpoint was achieving TSC after 12 weeks of IL-17 inhibitors treatment, defined as the 100% improvement in Psoriasis Area and Severity Index (PASI 100). Multivariate Cox regression analyses and LASSO analysis were performed to identify clinical predictors and blood predictors respectively. RESULTS: The following parameters were identified as predictive factors associated with TSC: previous biologic treatment, joint involvement, genital area affected, early response (PASI 60 at week 4), neutrophil counts and uric acid levels. The nomogram model incorporating these factors achieved good discrimination in the development cohort (AUC, 0.721; 95% CI 0.670-0.773) and validation cohort (AUC, 0.715; 95% CI 0.665-0.760). The calibration curves exhibited a satisfactory fit, indicating the accuracy of the model. Furthermore, the decision curve analysis confirmed the clinical utility of the nomogram, highlighting its favorable value for practical application. Web-based online calculator has been developed to enhance the efficiency of clinical applications. CONCLUSIONS: This study developed a practical and clinically applicable nomogram model for the prediction of TSC in patients with moderate to severe psoriasis. The nomogram model demonstrated robust predictive performance and exhibited significant clinical utility. Trial registration A multi-center clinical study of systemic treatment strategies for psoriasis in Chinese population;ChiCTR2000036186; Registered 31 August 2020; https://www.chictr.org.cn/showproj.html?proj=58256 .

Biologics targeting IL-17 and IL-23 maintain stability in patients with psoriasis during COVID-19 infection: a case-control study.

Background: Psoriasis is a chronic and refractory skin disease. The emergence of biologics provides more options for the treatment of psoriasis, but the COVID-19 pandemic poses challenges for the management of psoriasis. Objectives: The purpose of this study was to investigate the effect of different biologics on the stabilization of psoriasis during COVID-19 infection in China. Methods: This is a single-center, observational, retrospective, case-control study. Using our database, we conducted a remote dermatologic study by means of questionnaire follow-up or telephone follow-up to collect general information of patients, information related to COVID-19 infection and conditions of psoriasis for comparison and further analysis between groups. Results: Our study ultimately included 274 patients for analysis. We found that the patients in this collection had mild symptoms of COVID-19 infection, and only 13 of them needed to go to the hospital for medical treatment. Further studies found that in biologics, relative to tumor necrosis factor-α inhibitors (TNF-αi), interleukin-17 inhibitors (IL-17i) and interleukin-23 inhibitors (IL-23i) are both protective factors in flare-up of psoriasis [IL-17i: OR (95% CI) = 0.412 (0.189-0.901); IL-23i: OR (95% CI) = 0.291 (0.097-0.876)]. In addition, we also found that the proportion of people with increased psoriasis developing long COVID-19 increased, and we speculated that increased psoriasis may be a potential risk factor for long COVID-19. Conclusion: Our study showed that the use of IL-17i and IL-23i was a protective factor for psoriasis compared with TNF-αi, and could keep the psoriasis stable.

A prospective randomized half-body study: 308 nm LED light vs. 308 nm excimer laser for localized psoriasis.

Background: Psoriasis is a chronic skin disease affecting approximately 3.2% of the population. The 308 nm light emitting diode (LED) is a novel, portable, and cost-effective light source, may have potential in the treatment of localized psoriasis patients in a home setting. Objective: To compare the clinical and dermoscopic responses in localized psoriatic patients undergoing localized phototherapy with 308 nm LED light and excimer laser. Methods: Twenty-two patients with mild-to-moderate psoriasis and symmetrical skin lesions were included in this prospective, randomized, left-to-right body trial. The target lesions were randomly treated with either LED light or excimer laser twice a week for 12 weeks. The responses were evaluated by the local psoriasis severity index (LPSI) scores, and dermoscopic features of the target lesions were examined and analyzed. Results: Out of the 22 included psoriasis patients, 10 successfully completed the 12 weeks study. Both treatment sides showed similar clinical improvement in terms of clinical response, as evidenced by a LPSI 50 rate of 70% on the LED side and 80% on the excimer side, p > 0.05. Furthermore, the dermoscopic features also exhibited comparable improvement. Conclusion: The efficacy and safety of 308 nm LED light therapy are comparable to 308 nm excimer laser therapy. Moreover, given the portability and cost-effectiveness of 308 nm LED light, it holds great promise as a home phototherapy in the treatment of psoriasis.

Long-term efficacy and safety of dupilumab for severe bullous pemphigoid: A prospective cohort study.

BACKGROUND: Bullous pemphigoid (BP) is a common subepidermal bullous disease. Dupilumab is a novel treatment for BP. However, its long-term efficacy and safety have not been demonstrated in prospective studies. OBJECTIVE: Evaluate the long-term efficacy and safety of dupilumab in treating severe BP. METHODS: Patients were divided into two groups: the methylprednisolone monotherapy group (M), and the methylprednisolone and dupilumab combination therapy group (D + M). This study consisted of two stages. The first stage focused on the initial treatment phase, where the early efficacy and safety was evaluated. The study then entered the 12-month maintenance treatment stage, where we assessed recurrence in both groups. Additionally, we evaluated the rate of healing of skin lesions, glucocorticoids burden and length of hospital stay and various laboratory test indicators. RESULTS: After four weeks of treatment, the Bullous Pemphigoid Disease Area Index (BPDAI) and pruritus Numerical Rating Scale scores of the D + M group decreased significantly more than those of the M group. The median BPDAI at week 4 was 0 (range: 0.0-3.0) in the D + M group and 10.0 (5.0-12.0) in the M group (P < 0.001). Patients treated with dupilumab experienced a faster cessation of new blisters, quicker glucocorticoid reduction, shorter healing times, and shorter hospital stays (P < 0.001). Additionally, after two weeks of treatment, the levels of eosinophils and immunoglobulin E also decreased (P < 0.001). Follow-up studies further demonstrated that dupilumab monotherapy was associated with a lower recurrence rate. Notably, no serious adverse effects were observed in the study. CONCLUSIONS: Our study provides evidence for the efficacy of dupilumab in the treatment of BP based on prospective studies. Additionally, our findings suggest that dupilumab can be considered a reliable single-agent maintenance treatment due to its good safety profile and lower relapse.

Ixekizumab four-week dosing is comparable to two-week dosing in psoriasis patients and reduces treatment costs: experience in a real-world setting over a 12-week period

Background: Little is known about different Ixekizumab (IXE) dosing regimens during routine clinical practice. Objectives: To evaluate the real-world effectiveness and safety of different IXE dosing regimens in patients with psoriasis. Materials & Methods: This study retrospectively compared patients who were dosed with IXE every two or four weeks (80 mg/week following a starting dose of 160 mg at Week 0). At Weeks 0, 4, and 12, the Psoriasis Area and Severity Index (PASI) and the Dermatology Life Quality Index (DLQI) were recorded, with adverse events also documented. Results: In total, 66 patients were analysed, of whom 30 (45.5%) and 36 (54.5%) were included in the two-week and four-week IXE dosing groups, respectively. In the overall patient cohort, 86.3%, 60.6%, and 31.8% exhibited PASI 75, PASI, 90, and PASI 100 responses at Week 12, respectively. The mean baseline PASI score was 12.4±7.6 and the mean baseline DLQI score was 11.3±6.9, with these values declining rapidly following IXE administration to 1.6±2.4, and 2.6±4.0 at Week 12, respectively. Response rates were elevated in the two-week group as compared to the four-week group at Weeks 4 and 12 of treatment, but these differences were not significant. Adverse events were reported in 25 patients (37.9%), with injection site reactions being most common, followed by infections. Conclusion: IXE is effective and safe in a real-world setting for the treatment of plaque psoriasis. Moreover, patients can reduce their medical expenses by choosing a four-week dosing regimen while still attaining therapeutic benefits.

Drug Survival Outcomes Associated with the Real-World Use of Ixekizumab, Secukinumab, Guselkumab, and Adalimumab for the Treatment of Plaque Psoriasis in China: A 52-Week Single-Center Retrospective Study.

Background: Data pertaining to biologic agents used for treating psoriasis in real-world settings are lacking at present. To compare drug survival at 52 weeks for a range of biologics used to treat psoriasis under real-world conditions. Methods: This was a retrospective, single-center, observational study of a cohort of patients diagnosed with plaque psoriasis treated using ixekizumab, secukinumab, guselkumab, or adalimumab between January 2020 and December 2021. Baseline demographic characteristics, duration of psoriasis, and prior biological treatments for all patients were recorded. Drug survival rates were analyzed in different patient groups using Kaplan-Meier curves and Log rank tests. Results: In total, this study included 386 plaque psoriasis patients, of whom 70, 175, 36, and 105 were, respectively, treated using ixekizumab, secukinumab, guselkumab, and adalimumab. Over a 52-week period, the overall cumulative drug survival rates for ixekizumab, secukinumab, guselkumab, and adalimumab were 67.1%, 63.0%, 72.2%, and 37.1%, respectively. Lack of efficacy was the primary cause of discontinuation for these biologic therapies, followed by economic burden and adverse event incidence. Conclusion: These results suggest that guselkumab exhibited superior drug survival, drug survival outcomes for ixekizumab and secukinumab were comparable, and significantly better than those of adalimumab in China. Preventing a loss of drug efficacy represents a primary approach to improving biologic drug survival in psoriasis patients.

IL-17A Promotes Psoriasis-Associated Keratinocyte Proliferation through ACT1-Dependent Activation of YAP-AREG Axis.

Psoriasis is a recurrent inflammatory skin disorder characterized by epidermal hyperplasia, which is primarily driven by IL-17A. The Hippo-YAP signaling pathway plays a vital role in cell survival and tissue growth, and its target gene, AREG, has been reported to promote the development of psoriasis. However, whether IL-17A promotes keratinocyte proliferation through regulating Hippo-YAP signaling has not been explored. In this study, we show that the YAP-AREG pathway is activated in human psoriatic skin and is suppressed by IL-17A antagonist secukinumab and that imiquimod and IL-17A administration activates the YAP-AREG axis in mice epidermis. In vitro studies using HaCaT and normal human epidermal keratinocyte cells suggest that IL-17A enhances AREG expression and keratinocyte proliferation by activating Hippo-YAP signaling. Mechanistically, IL-17A stimulates the recruitment of MST1 to ACT1 in keratinocytes, which leads to reduced MST1-LATS1 interaction and YAP dephosphorylation. Together, our findings reveal a previously unknown mechanism in which IL-17A promotes keratinocyte proliferation in psoriasis, namely through activating YAP-AREG signaling.

The roles of AMPK-mediated autophagy and mitochondrial autophagy in a mouse model of imiquimod-induced psoriasis.

BACKGROUND: Psoriasis is a systemic inflammatory disease characterized by epidermal hyperplasia and skin inflammatory infiltrates. Inactivation of AMPK has been shown to decrease autophagy, thereby inhibiting elimination of inflammatory factors and harmful substances, and aggravating psoriasis. However, the molecular mechanism through which AMPK affects psoriasis remains to be further explored. In this study, we investigated whether AMPK regulates autophagy through the ULK1/Atg7 signaling pathway and regulates mitochondrial autophagy through the PINK1/Parkin signaling pathway, thereby affecting a mouse model of psoriasis. METHODS: Imiquimod was used to induce psoriasis-like lesions on the backs of mice. The severity of skin lesions in psoriatic mice was evaluated with the skin inflammation severity score, and epidermal thickness was measured on the basis of H&E staining. RT-PCR, western blotting and immunofluorescence staining were used to detect indicators of autophagy and mitochondrial autophagy. RESULTS: AMPK activity was inhibited in the psoriasis mouse model, the autophagy-associated proteins ULK1/Atg7 were inhibited, and the mitochondrial autophagy proteins PINK1/Parkin were also decreased. Results indicated that autophagy and mitochondrial autophagy were inhibited in the mouse model. When AMPK signaling was upregulated, ULK1/Atg7 and PINK1/Parkin were upregulated, autophagy and mitochondrial autophagy increased, and skin lesions in the mouse model were alleviated. ULK1/Atg7 and PINK1/Parkin were down-regulated when AMPK signaling was downregulated, and psoriasis-like skin lesions were aggravated in mice. These results indicated that AMPK regulates autophagy through the ULK1/Atg7 signaling pathway and regulates mitochondrial autophagy through the PINK1/Parkin signaling pathway, thus affecting the prognosis of psoriasis in the mouse model. CONCLUSION: AMPK affects the prognosis of psoriasis in a mouse model by regulating autophagy and mitochondrial autophagy.

Infliximab modifies regulatory T cells and co-inhibitory receptor expression on circulating T cells in 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-α (TNF-α) 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-α. 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-α 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.

High-throughput transcriptome and pathogenesis analysis of clinical psoriasis.

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.

Interleukin-33 alleviates psoriatic inflammation by suppressing the T helper type 17 immune response.

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.

IL-21 Induces an Imbalance of Th17/Treg Cells in Moderate-to-Severe Plaque Psoriasis Patients.

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.