Active Heme Metabolism Suppresses Macrophage Phagocytosis via the TLR4/Type I IFN Signaling/CD36 in Uterine Endometrial Cancer.

BACKGROUND: Uterine endometrial cancer (UEC) is a common gynecological estrogen-dependent carcinoma, usually accompanied by intermenstrual bleeding. Active heme metabolism frequently plays an increasingly important role in many diseases, especially in cancers. Tumor-associated macrophages (TAMs) are the major population in the immune microenvironment of UEC. However, the roles of heme metabolisms in the crosstalk between UEC cells (UECCs) and macrophages are unclear. MATERIALS AND METHODS: In our study, by using TCGA database analysis, integration analysis of the protein-protein interaction (PPI) network and sample RNA transcriptome sequencing were done. The expression level of both heme-associated molecules and iron metabolism-related molecules were measured by quantitative real-time polymerase chain reaction. Heme level detection was done through dehydrohorseradish peroxidase assay. In addition to immunohistochemistry, phagocytosis assay of macrophages, immunofluorescence staining, intracellular ferrous iron staining, as well as enzyme-linked immune sorbent assay were performed. RESULTS: In the study, we verified that heme accumulation in UECCs is apparently higher than in endometrial epithelium cells. Low expression of succinate dehydrogenase B under the regulation of estrogen contributes to over-production of succinate and heme accumulation in UECC. More importantly, excessive heme in UECCs impaired macrophage phagocytosis by regulation of CD36. Mechanistically, this process is dependent on toll-like receptor (TLR4)/type I interferons alpha (IFN Iα) regulatory axis in macrophage. CONCLUSION: Collectively, these findings elucidate that active heme metabolism of UECCs directly decreases phagocytosis by controlling the secretion of TLR4-mediated IFN Iα and the expression of CD36, and further contributing to the immune escape of UEC.

IL-27 disturbs lipid metabolism and restrains mitochondrial activity to inhibit γδ T17 cell-mediated skin inflammation.

IL-17+ γδ T cells (γδ T17) are kick-starters of inflammation due to their strict immunosurveillance of xenobiotics or cellular damages and rapid response to pro-inflammatory stimulators. IL-27 is a well-recognized pleiotropic immune regulator with potent inhibitory effects on type 17 immune responses. However, its actions on γδ T17 mediated inflammation and the underlying mechanisms are less well understood. Here we find that IL-27 inhibits the production of IL-17 from γδ T cells. Mechanistically, IL-27 promotes lipolysis while inhibits lipogenesis, thus reduces the accumulation of lipids and subsequent membrane phospholipids, which leads to mitochondrial deactivation and ensuing reduction of IL-17. More importantly, Il27ra deficient γδ T cells are more pathogenic in an imiquimod-induced murine psoriasis model, while intracutaneous injection of rmIL-27 ameliorates psoriatic inflammation. In summary, this work uncovered the metabolic basis for the immune regulatory activity of IL-27 in restraining γδ T17 mediated inflammation, which provides novel insights into IL-27/IL-27Ra signaling, γδ T17 biology and the pathogenesis of psoriasis.

Advantages of ultrasound imaging for the early diagnosis of psoriatic arthritis in patients with moderate to severe psoriasis.

Background: Psoriatic arthritis (PsA) is an immune-mediated form of chronic inflammatory arthritis associated with psoriasis (PsO). It constitutes a significant comorbidity of PsO and is distinguished by the presence of widespread musculoskeletal inflammation. Objective: The aim of this study is to precisely detect asymptomatic PsA using ultrasound (US) examinations and to distinguish between various stages of PsO. Methods: All patients with moderate-to-severe PsO, who consented to undergo musculoskeletal US examinations during their hospitalization between September 2020 and January 2022, were enrolled in the study. We compared patients' demographic characteristics, comorbidities, disease duration, relevant laboratory parameters, and musculoskeletal US findings. Results: A total of 547 patients with PsO were included in the study, and 114 of them received a diagnosis of PsA. Furthermore, 16.45 % of patients with moderate to severe PsO displayed subclinical PsA. We observed a significantly higher frequency of abnormal US findings in patients with PsA compared to those without PsA, with a sensitivity of 95.61 % and a specificity of 79.22 %. Additionally, the incidence of enthesitis and synovitis varied significantly between PsA and non-PsA patients, and they were identified as independent variables predicting the presence of PsA. Furthermore, the interphalangeal joint, knee joint, and calcaneal tendon were the most frequently affected areas in PsA, as indicated by the observed US changes. Conclusion: Ultrasound examination proves to be a valuable tool for detecting subclinical PsA, facilitating early screening of the condition. Particular attention should be directed towards changes in the interphalangeal joint, knee joint, and calcaneal tendon when reviewing ultrasound images of asymptomatic patients.

Heme metabolism and HO-1 in the pathogenesis and potential intervention of endometriosis.

Endometriosis (EM) is one of the diseases related to retrograded menstruation and hemoglobin. Heme, released from hemoglobin, is degraded by heme oxygenase-1 (HO-1). In EM lesions, heme metabolites regulate processes such as inflammation, redox balance, autophagy, dysmenorrhea, malignancy, and invasion, where macrophages (Mø) play a fundamental role in their interactions. Regulation occurs at molecular, cellular, and pathological levels. Numerous studies suggest that heme is an indispensable component in EM and may contribute to its pathogenesis. The regulatory role of heme in EM encompasses cytokines, signaling pathways, and kinases that mediate cellular responses to external stimuli. HO-1, a catalytic enzyme in the catabolic phase of heme, mitigates heme's cytotoxicity in EM due to its antioxidant, anti-inflammatory, and anti-proliferative properties. Certain compounds may intervene in EM by targeting heme metabolism, guiding the development of appropriate treatments for all stages of endometriosis.

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.

Insulin resistance impairs biologic agent response in moderate-to-severe plaque psoriasis: insights from a prospective cohort study in China.

BACKGROUND: Psoriasis and insulin resistance (IR) are closely related, but it remains unclear whether IR affects the treatment of patients with psoriasis. OBJECTIVE: To investigate whether IR impairs the treatment response to biologic agents in patients with moderate-to-severe plaque psoriasis. METHODS: This project was based on a prospective cohort study design. Data were collected from the Shanghai Psoriasis Effectiveness Evaluation CoHort (SPEECH), which is a prospective cohort exploring treatment strategies for psoriasis in China. IR was assessed using triglyceride glucose-body mass index (TyG-BMI). Psoriasis severity was assessed using Psoriasis Area and Severity Index (PASI) and Physician Global Assessment (PGA). Multiple logistic regression was used to explore the differences between patients with high and low levels of IR. Subgroup and sensitivity analyses were performed to examine the robustness of the study results. RESULTS: A total of 290 patients were included in the analysis. Based on median TyG-BMI, the patients were divided into two groups: high and low IR. The high IR group exhibited a higher prevalence of diabetes, a higher BMI, and higher fasting blood glucose and triglyceride levels than the low IR group. Further analysis of treatment efficacy revealed that patients in the high IR group had lower PASI 75 [≥ 75% improvement in Psoriasis Area and Severity Index (PASI)], PASI 90 (≥ 90% improvement in PASI) and PGA 0/1 ('clear' or 'almost clear') response rates after 12 weeks of treatment. In the low IR group, 81.9% of patients achieved PASI 75, 58.3% achieved PASI 90 and 75.7% achieved PGA 0/1. However, the proportion of responses at each endpoint was significantly lower in the high IR group compared with the low IR group. The reduced PGA 0/1 response rate was more significant in the high IR group, indicated by lower odd ratios. Subsequent subgroup and sensitivity analyses produced consistent results. CONCLUSION: IR is associated with lower effectiveness of biologics in patients with psoriasis.

Psoriasis is a chronic and recurrent inflammatory skin disease mediated by T cells. Psoriasis not only impacts on the skin, but it also affects other body parts such as the joints. Historically, the treatment of psoriasis has been challenging. However, with advancements in research looking at how the immune system works and the development of biological agents (a type of drug), treatments for psoriasis have undergone profound changes. 'Biologics', as they are called, have shown remarkable improvements in psoriasis, including complete skin clearance. However, some people with psoriasis experience a poor or no response to treatment. Previous research has explored which factors may affect treatment response, including obesity and diabetes. In addition, insulin resistance plays a central role in the development of obesity and diabetes. We conducted the Shanghai Psoriasis Effectiveness Evaluation CoHort (SPEECH) study in China to investigate the effect of insulin resistance on the response to biologics in people with psoriasis. In our study, we used the 'TyG-BMI' (which stands for 'triglyceride glucose­body mass index') as a tool to assess insulin resistance and divided patients into 'high insulin resistance' and 'low insulin resistance' groups. Psoriasis severity was assessed using tools called the Psoriasis Area and Severity Index (PASI) and the Physician Global Assessment (PGA). Fewer people in the high insulin resistance group achieved a 75% or more improvement in PASI (PASI 75), a 90% or more improvement in PASI (PASI 90) and a PGA score of 'clear' or 'almost clear' (PGA 0/1) after 12 weeks of treatment. The reduced response to PGA 0/1 was more noticeable in the high insulin resistance group. We also carried out further analyses that supported these findings. Overall, our findings provide evidence that insulin resistance can hinder the effectiveness of biologics in some people with psoriasis.

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 .

Decreased risk of COVID-19 and long COVID in patients with psoriasis receiving IL-23 inhibitor: A cross-sectional cohort study from China.

Background: Although clinical trials and real-world data suggest that the risk of COVID-19 and its complications is not exacerbated in patients with psoriasis treated by biological agents, the evidence for this is still limited. Objectives: We aimed to assess the outcomes of COVID-19 among Chinese patients with psoriasis treated by IL-23 inhibitor, and to compare these variables in patients receiving other therapies. Methods: A cross-sectional cohort study was conducted to compare psoriasis treatment with IL-23 inhibitor to other treatment methods. All the patients received a questionnaire that contained questions about their psoriasis treatment, COVID-19 symptoms, and related risk factors. The prevalence of COVID-19 was calculated, and logistic regression analyses were performed to determine the association between treatment method and COVID-19 risk. The symptoms of COVID-19 and long COVID were described for each treatment group. Results: Between December 2022 and February 2023, 732 patients with psoriasis were included in the final analysis. 549 patients had a SARS-CoV-2 infection during the study period. Our results showed that individuals who worked outdoors had a decreased risk of COVID-19, as did those who had other allergic disease. With regard to the effect of the treatment regimens, IL-23 inhibitor treatment was associated with a decreased risk of COVID-19 compared to almost all the other treatments except acitretin. Fever was the most common symptom, but the maximum temperature and duration of fever were comparable among the treatment groups. Patients treated with IL-23 inhibitor were more likely to be asymptomatic after recovery compared to patients treated with methotrexate, narrow-bound ultra violet B, or TNF-α inhibitor. Conclusions: IL-23 inhibitor treatment may lower the risk of COVID-19 and long COVID. Thus, IL-23 inhibitor treatment might be beneficial and positively considered for patients with psoriasis who require systemic treatment during periods when there is a surge in COVID-19 cases.

Improvement of Pruritus and Efficacy in the Early Stage of Therapy with Upadacitinib, Abrocitinib, or Dupilumab in Chinese Patients with Moderate-to-Severe Atopic Dermatitis: Prospective, Cohort, Observational Study.

Background: Atopic dermatitis (AD) is an immune system-mediated, complex skin disease. Additional treatment options are needed to provide a better and faster clinical response for patients with AD. Objective: Investigate the difference in efficacy for the rapid relief from pruritus in adults with moderate-to-severe AD. Methods: A 12-week prospective, cohort, observational, single-center study was conducted in adults with moderate-to-severe AD. Patients were assigned randomly (in a 1:1:1 ratio) to receive upadacitinib, abrocitinib, or dupilumab. Pruritus is a key symptom of AD, so the primary endpoint was a reduction in the weekly average worst pruritus Numerical Rating Scale (NRS) score by ≥3 points from baseline at week 4. In addition, we analyzed the response rate at each visit for 75% improvement in Eczema Area and Severity Index (EASI75) and validated Investigator's Global Assessment for Atopic Dermatitis 0/1 (vIGA-AD 0/1). Results: Baseline characteristics was balanced among treatment groups, including measures of disease severity. After 4 weeks of treatment, there was a significant increase in the proportion of patients treated with Janus kinase (JAK) inhibitors who experienced a reduction of ≥3 points in the NRS score compared with those receiving dupilumab. After further treatment, JAK inhibitors resulted in a further reduction of NRS in patients, with a higher percentage of patients achieving EASI75 and vIGA 0/1 (particularly upadacitinib). In addition, no additional serious adverse events were observed during the 12-week follow-up period. Conclusions: JAK inhibitors could be considered as effective treatment options for patients with moderate-to-severe AD, particularly upadacitinib, which has shown the greatest efficacy in reducing itching with a favorable safety profile.

Improvement of parents' oral health knowledge by a school-based oral health promotion for parents of preschool children: a prospective observational study.

BACKGROUND: Parents of preschool children have inadequate oral health knowledge in Hong Kong. Parents play a critical role in preschool children's dietary patterns and oral health behaviors. A school-based oral health promotion (OHP) for parents of preschoolers was developed and investigated. OBJECTIVES: The objective of this study was to evaluate effects of the school-based OHP for parents of preschool children on parents' oral health knowledge and preschool children's early childhood caries (ECC). MATERIALS AND METHODS: This was a quasi-experimental study. Parents of preschool children were divided into the intervention group (IG) and the control group (CG) according to their own selection. Parents in the IG participated in a structured school-based OHP workshop, while those in the CG did not attend the OHP workshop. Parents in both groups were invited to complete a questionnaire assessing their oral health knowledge before (T0), one month after (T1), and twelve months after (T2) the OHP workshop. Preschool children's caries was examined via dmft score at T0 and T2. RESULTS: Parents' oral health knowledge was negatively correlated with preschool children's dmft scores (R = -0.200, P < 0.001). Oral health knowledge was significantly improved in IG (P < 0.001) but not in CG (P = 0.392) at T1. Both groups experienced a significant improvement in oral health knowledge from T0 to T2 (P < 0.001). Parents' oral health knowledge in the IG was significantly higher compared to the CG at T1 (P < 0.001), but difference in the scores at T2 between the two groups showed no significant difference (P = 0.727). No significant difference was found in changes in children's dmft score from T0 to T2 between the IG and CG (p = 0.545). CONCLUSION: Preschool children's high ECC is associated with the limited oral health knowledge of their parents. The school-based OHP workshop for parents increased parents' oral health knowledge within one month. This positive effect was maintained for twelve months and can be extended to a larger scale in the school setting.

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.

Janus kinase inhibitors in autoimmune bullous diseases.

Autoimmune bullous disease (AIBD) is a severe skin disorder caused by autoantibodies that target intercellular or cell-matrix adhesion proteins. Currently, the preferred treatment for AIBD involves the use of glucocorticoids or traditional immunosuppressants. Additionally, the utilization of biological agents such as rituximab, omalizumab, and dupilumab is on the rise. However, effectively managing AIBD remains a challenge. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway has been implicated in various inflammatory diseases. In recent years, a range of drugs known as JAK inhibitors, which target this pathway, have been developed. Several studies have explored the efficacy and safety of JAK inhibitors for treating AIBD. Consequently, this review begins by examining the role of the JAK/STAT pathway in AIBD, summarizing the application of different JAK inhibitors in AIBD treatment, and emphasizing the importance of disease management in treating AIBD with JAK inhibitors. Furthermore, it highlights the need for a better understanding of the JAK/STAT pathway's role in AIBD, as well as the effectiveness and safety of JAK inhibitors for treating this disease.

Active Estrogen-Succinate Metabolism Promotes Heme Accumulation and Increases the Proliferative and Invasive Potential of Endometrial Cancer Cells.

Uterine endometrial cancer (UEC) is an estrogen-related tumor. Succinate and heme metabolism play important roles in the progression of multiple tumors. However, the relationship between estrogen, succinate, and heme metabolism and related regulatory mechanisms remain largely unknown. In this study, we observed that the expression of aminolevulinate delta synthase 1 (ALAS1) and solute carrier family member 38 (SLC25A38) in UEC tissues is significantly higher than that in normal tissues. Further analysis showed that estrogen and succinate increased the expression of ALAS1 and SLC25A38 in uterine endometrial cancer cells (UECC), and the administration of succinate upregulated the level of the estrogen receptor (ER). Silencing nuclear receptor coactivator 1 (NCOA1) reversed the effects of estrogen and succinate via downregulation of ALAS1 expression. Additionally, exposure of UECC to heme increased cell viability and invasiveness, while silencing the NCOA1 gene weakened this effect. These findings revealed that estrogen and succinate can synergistically increase the expression of ALAS1 and SLC25A38 via the ERß/NCOA1 axis, promoting heme accumulation and increasing the proliferative and invasive potential of UECC.

Quality of Life Benefit and Clinical Predictors of Complete Skin Clearance in Psoriasis: A Multicenter, Prospective, Real-World Study.

BACKGROUND: Newer biologics, such as interleukin (IL)-17 inhibitors, make it possible to achieve complete skin clearance (CSC) in patients with moderate-to-severe psoriasis. However, the clinical meaningfulness and predictive factors of CSC in daily practice have not yet been fully investigated. OBJECTIVE: The study was conducted to, first, assess the impact of CSC on quality of life (QoL) improvements compared with treatment responses without clearance and, second, identify clinical parameters as predictors of CSC response in psoriasis patients treated with ixekizumab. METHODS: Patients attending 26 dermatology centers across China were recruited into this real-world setting between August 2020 and May 2022. Prospective cohort study in which response to ixekizumab was assessed using the Psoriasis Area and Severity Index (PASI) and Dermatology Quality of Life Index (DLQI). The absolute DLQI score and DLQI (0) response at week 12 were compared between groups achieving various levels of skin clearance. A stepwise logistic regression analysis was applied to identify which baseline clinical characteristics were predictive factors for CSC. RESULTS: After 12 weeks of treatment, 226 of 511 (44.2%) patients achieved CSC, defined as 100% improvement in PASI score (PASI-100). A significantly higher proportion of patients with CSC versus almost clear skin (PASI 90-99) achieved DLQI score of 0, corresponding to the experience of no impairment on QoL (54.4% vs. 37.7%, p = 0.001). Females patients were more likely than males to achieve CSC response (odds ratio [OR] = 1.83; 95% confidence interval [CI]: 1.24-2.70), while previous biologic treatment (OR = 0.43; 95% CI: 0.24-0.81) and joint affected (OR = 0.61; 95% CI: 0.42-0.89) were significantly associated with less CSC response. CONCLUSIONS: This study highlights the fact that clinical parameters are important in determining CSC response in psoriasis. In daily practice, achieving CSC represents a clinically meaningful treatment goal, especially from the patient perspective.

Development of bullous pemphigoid during treatment of psoriasis with ustekinumab: a case report and literature review.

Ustekinumab is a biological therapy that has been approved for treating moderate-to-severe psoriasis. Although injection site reactions, nasopharyngitis, headaches, and infections are the common adverse events associated with ustekinumab, the development of bullous pemphigoid (BP) is also thought to be related to ustekinumab. Given that psoriasis itself can be complicated by BP, it is worthwhile to investigate the relationship between ustekinumab, psoriasis, and BP. Here we report a case of a male patient who developed BP twice after psoriasis treatment with ustekinumab. The patient's psoriasis and BP were brought under control by discontinuing ustekinumab and administering methotrexate, minocycline, and topical corticosteroids. Because of the increasing use of biologics in patients with psoriasis, BP should be considered a potential adverse event associated with ustekinumab.

TLR7-MyD88-DC-CXCL16 axis results neutrophil activation to elicit inflammatory response in pustular psoriasis.

Pustular psoriasis (PP) is a chronic inflammatory disease associated with multiple complications, often with hyperthermia and hypoproteinemia, and its continued progression can be life-threatening. Toll-like receptor 7 (TLR7) induces dendritic cell (DC) production of inflammatory factors that exacerbate the inflammatory response in PP. A membrane-bound chemokine expressed on DCs, CXC motif chemokine ligand 16 (CXCL16) is overexpressed in PP lesions, and neutrophils express its receptor CXC chemokine receptor 6 (CXCR6). There are few studies on the PP immune microenvironment and it is unclear whether TLR7 and CXCL16 can be used as targets in PP therapy. Skin tissue (n = 5) and blood (n = 20) samples were collected from PP and healthy normal controls. The skin tissue transcriptome was analyzed to obtain the differentially expressed genes, and the immune microenvironment was deciphered using pathway enrichment. Tissue sequencing analysis indicated that TLR7, CXCL16, DCs, and neutrophils were involved in the PP process. The enzyme-linked immunosorbent assay, reverse transcription-PCR, and scoring table results demonstrated that TLR7 induced DC secretion of CXCL16, which enabled neutrophil activation of the secretion of the inflammatory factors interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α). The co-culture of neutrophils with DCs treated with TLR7 inhibitor or TLR7 agonist demonstrated that TLR7 regulated neutrophil activation, migration, and apoptosis. We constructed imiquimod-induced psoriasis-like skin lesions in wild-type, Cd11c-Cre Myd88f/f, and Mrp8-Cre Cxcr6f/f mice. The mouse models suggested that TLR7 might influence DC release of CXCL16 and neutrophil proinflammatory effects by interfering with the myeloid differentiation primary response gene 88 (MyD88) signaling pathway. In conclusion, the TLR7-MyD88-DC-CXCL16 axis is an important mechanism that promotes neutrophil migration to PP skin lesions and stimulates the inflammatory response.

Circ_0082476 targets miR-138-5p to promote proliferation, invasion, migration and inflammation in IL-22-treated human keratinocytes by upregulating BRD4.

BACKGROUND: Circular RNAs (circRNAs) are implicated in the disease progression via acting as sponges of microRNAs (miRNAs) to regulate gene expression. The purpose of this study was to analyze the involvement of circ_0082476 in Interleukin-22 (IL-22)-induced psoriasis. METHODS: Expression detection for circ_0082476, microRNA-424-5p (miR-138-5p) or toll-like receptor (BRD4) was completed using reverse transcription-quantitative polymerase chain reaction assay. Cell Counting Kit-8 assay and EdU assay were used for analysis of cell viability and proliferation, respectively. Cell invasion and migration abilities were assessed through transwell assay and wound healing assay. The protein expression was examined via western blot. Inflammatory reaction was determined via Enzyme-linked immunosorbent assay. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were conducted for target binding research. RESULTS: Circ_0082476 was significantly elevated in psoriasis patients and IL-22-treated keratinocytes (HaCaT). Knockdown of circ_0082476 reduced cell proliferation, invasion and migration in IL-22-treated HaCaT cells. Circ_0082476 induced sponge effect on miR-138-5p. Circ_0082476 regulated IL-22-induced cell injury through targeting miR-138-5p. BRD4 was confirmed as a target of miR-138-5p, and miR-138-5p relieved IL-22-induced cell dysfunction by the direct downregulation of BRD4. BRD4 was positively regulated by circ_0082476 via sponging miR-138-5p. CONCLUSION: These findings disclosed that circ_0082476 facilitated the IL22-induced epidermis cell injury in psoriasis through the upregulation of BRD4 via binding to miR-138-5p.