Global and regional epidemiology of psoriatic arthritis in patients with psoriasis: A comprehensive systematic analysis and modelling study.

OBJECTIVES: To provide a comprehensive analysis and modelling of the global epidemiology of psoriatic arthritis (PsA) in patients with psoriasis. METHODS: We reviewed and analysed PsA epidemiology studies over the past 45 years. A Bayesian hierarchical linear mixed model was developed to provide comprehensive age- and sex-specific epidemiologic estimates in different countries and regions. RESULTS: Three hundred and sixty-three studies were systematically reviewed. The incidence of PsA in patients with psoriasis varied from 2.31 per 1000 person-years in the United Kingdom to 74.00 per 1000 person-years in several Western European countries. The global prevalence of PsA in patients with psoriasis is estimated to be 17.58% (3.33%, 43.69%). Regionally, the overall prevalence of PsA in patients with psoriasis varies from 7.62% (4.18%, 12.28%) in Australasia to 26.59% (18.89%, 35.76%) in North America. The Caribbean and Central Latin America also have relatively high prevalence and are estimated at 23.14% (14.06%, 35.17%) and 22.81% (14.36%, 32.25%), respectively. The prevalence of PsA is higher in adults than children (23.93% vs 8.59%) and also slightly higher in females than males (19.14% vs 16.01%). CONCLUSIONS: This study provides valuable insights into the global epidemiology of PsA. It also serves as a useful resource for researchers in areas lacking relevant studies. These findings have important implications for clinicians managing the course of PsA and for health policymakers in resource allocation.

Cannabinoid receptor 2 selective agonist alleviates systemic sclerosis by inhibiting Th2 differentiation through JAK/SOCS3 signaling.

Systemic sclerosis (SSc) poses a significant challenge in autoimmunology, characterized by the development of debilitating fibrosis of skin and internal organs. The pivotal role of dysregulated T cells, notably the skewed polarization toward Th2 cells, has been implicated in the vascular damage and progressive fibrosis observed in SSc. In this study, we explored the underlying mechanisms by which cannabinoid receptor 2 (CB2) highly selective agonist HU-308 restores the imbalance of T cells to alleviate SSc. Using a bleomycin-induced SSc (BLM-SSc) mouse model, we demonstrated that HU-308 effectively attenuates skin and lung fibrosis by specifically activating CB2 on CD4+ T cells to inhibit the polarization of Th2 cells in BLM-SSc mice, which was validated by Cnr2-specific-deficient mice. Different from classical signaling downstream of G protein-coupled receptors (GPCRs), HU-308 facilitates the expression of SOCS3 protein and subsequently impedes the IL2/STAT5 signaling pathway during Th2 differentiation. The deficiency of SOCS3 partially mitigated the impact of HU-308. Analysis of a cohort comprising 80 SSc patients and 82 healthy controls revealed an abnormal elevation in the Th2/Th1 ratio in SSc patients. The proportion of Th2 cells showed a significant positive correlation with mRSS score and positivity of anti-Scl-70. Administration of HU-308 to PBMCs and peripheral CD4+ T cells from SSc patients led to the upregulation of SOCS3, which effectively suppressed the aberrantly activated STAT5 signaling pathway and the proportion of CD4+IL4+ T cells. In conclusion, our findings unveil a novel mechanism by which the CB2 agonist HU-308 ameliorates fibrosis in SSc by targeting and reducing Th2 responses. These insights provide a foundation for future therapeutic approaches in SSc by modulating Th2 responses.

Equivalent cut-off values of Bath Ankylosing Spondylitis Disease Activity Index corresponding to Ankylosing Spondylitis Disease Activity Score cut-off values.

OBJECTIVES: To define the equivalent cut-off values of Bath ankylosing Spondylitis Disease Activity Index (BASDAI) for discriminating disease activity corresponding to Ankylosing Spondylitis Disease Activity Score (ASDAS) cut-off values, and to determine the equivalent change units for determining the clinically improvement between ΔBASDAI and ΔASDAS-CRP. METHODS: 475 patients with axial spondyloarthritis (axSpA) whose data on BASDAI and ASDAS were available were included. Among them, 154 (32.4%) patients whose data on ΔBASDAI and ΔASDAS-CRP were available. Receiver-operator curve (ROC) with area under curve (AUC) was used to determine the BASDAI cut-off values that best corresponded to ASDAS-CRP. The Cohen's kappa was utilised to assess the degree of agreement between disease activity states based on BASDAI and ASDAS cut-off values, and clinically improvement between ΔBASDAI and ΔASDAS-CRP. RESULTS: According to the ASDAS-CRP, 88 (18.6%), 130 (27.4%), 191 (40.1%) and 66 (13.9%) patients were classified as inactive, moderate, high and very high disease activities, respectively. ROC revealed that BASDAI values 1.6 (AUC: 0.948), 2.9 (AUC: 0.790) and 3.8 (AUC: 0.875) best corresponded to ASDAS-CRP values 1.3, 2.1 and 3.5, respectively. The degree of agreement between them was moderate (kappa: 0.527). The ΔBASDAI 1.6 (AUC: 0.745) and 2.0 (AUC: 0.708) best corresponded to the ΔASDAS-CRP 1.1 (minimal clinically important improvement) and 2.0 (major improvement), respectively. The degree of agreement was good (kappa: 0.685). CONCLUSIONS: The BASDAI values 1.6, 2.9 and 3.8 correspond to ASDAS-CRP values 1.3, 2.1 and 3.5, respectively. The ΔBASDAI 1.6 and 2.0 best correspond to the ΔASDAS-CRP 1.1 and 2.0, respectively.

Cutting Edge: Inhibition of Glycogen Synthase Kinase 3 Activity Induces the Generation and Enhanced Suppressive Function of Human IL-10+ FOXP3+-Induced Regulatory T Cells.

IL-10 is critical for Foxp3+ regulatory T cell (Tregs)-mediated immune suppression, but how to efficiently upregulate IL-10 production in Tregs remains unclear. In this article, we show that human IL-10+ FOXP3+-induced regulatory T cell (iTreg) generation can be dramatically promoted by inhibiting GSK3 activity. IL-10+ FOXP3+ iTregs induced by GSK3 inhibition exhibit classical features of immune-suppressive T cells. We further demonstrate that IL-10+ iTregs exhibit enhanced suppressive function in both IL-10-dependent and -independent manners. The enhanced suppressive function of IL-10+ Tregs is not due to a single factor such as IL-10, although IL-10 may mediate this enhanced suppressive function to some extent. Mechanistically, the increased transcriptional activity of IL-10 promoter and the enhanced expression of C-Maf and BLIMP1 coordinately facilitate IL-10 expression in human iTregs under GSK3 inhibition. Our study provides a new strategy to generate human immune-suppressive IL-10+ FOXP3+ Tregs for immunotherapies.

COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression.

A novel coronavirus disease (COVID-19), caused by infection with SARS-CoV-2, has swept across 31 provinces in China and over 40 countries worldwide. The transition from first symptoms to acute respiratory distress syndrome (ARDS) is highly likely to be due to uncontrolled cytokine release. There is an urgent need to identify safe and effective drugs for treatment. Chloroquine (CQ) exhibits a promising inhibitory effect. However, the clinical use of CQ can cause severe side effects. We propose that hydroxychloroquine (HCQ), which exhibits an antiviral effect highly similar to that of CQ, could serve as a better therapeutic approach. HCQ is likely to attenuate the severe progression of COVID-19, inhibiting the cytokine storm by suppressing T cell activation. It has a safer clinical profile and is suitable for those who are pregnant. It is cheaper and more readily available in China. We herein strongly urge that clinical trials are performed to assess the preventive effects of HCQ in both disease infection and progression.

C10orf116 Gene Copy Number Loss in Prostate Cancer: Clinicopathological Correlations and Prognostic Significance.

BACKGROUND Prostate cancer (PCa) is the second most commonly diagnosed cancer in males worldwide. This study aimed to identify differentially expressed genes and to investigate the potential correlation between gene abnormalities and clinical features in PCa to evaluate disease progression and prognosis. MATERIAL AND METHODS A total of 4 independent microarrays of PCa patients from the Oncomine database were used to identify differences in expression of genes contributing to cancer progression. Quantitative real-time polymerase chain reaction (RT-qPCR) analysis was used to evaluate the mRNA expression of the target in human prostate cancer cells. To explore the relationship between the DNA copy number alteration and mRNA expression changes, dataset containing copy number alteration, DNA methylation, and gene expression in PCa were obtained from the cBioPortal online platform (n=273). RESULTS We identified 40 genes that were significantly dysregulated in PCa from 4 independent microarrays. Among these, 3 genes showed a consistent change of over 2-fold in the 4 microarrays. The mRNA expression of C10orf116 showed consistent expression in prostate cancer cells compared with that in prostate gland cells as assessed by RT-qPCR. Moreover, C10orf116 loss was associated with poor distant relapse-free survival (DFS) by analyzing data of 273 PCa patients, but it was not identified as an independent prognostic risk factor for DFS. In addition, we found that C10orf116 loss was associated with higher pathological stage, higher clinical stage, and lymph node metastasis in PCa, and that C10orf116 copy number was highly correlated with PTEN copy number and mRNA expression. CONCLUSIONS As a predictive indicator, C10orf116 loss contributes to our understating of the biology of aggressive changes in PCa and also helps evaluate the prognosis of patients.

Different Modulatory Effects of IL-17, IL-22, and IL-23 on Osteoblast Differentiation.

OBJECTIVES: To examine the expressions of IL-17, IL-22, and IL-23 receptors in four osteoblast models and the effects of IL-17, IL-22, and IL-23 on osteoblasts. METHODS: Gene expression levels of receptors, alkaline phosphatase (ALP), osteocalcin (OCN), and Runt-related transcription factor 2 (Runx-2), were evaluated by RT-PCR and real-time RT-PCR. Proliferative responses and cell cycle analysis were detected by a CCK-8 assay and flow cytometry, respectively. ALP activity and ALP mass were detected by an ALP activity assay and ALP staining, respectively. RESULTS: In primary osteoblasts, only the IL-17 receptor was expressed. In C2C12, MC3T3-E1, and Saos-2 cells, the genes of IL-17, IL-22, and IL-23 receptors were not detectable. None of IL-17, IL-22, and IL-23 had an obvious effect on the proliferation of primary osteoblasts, but IL-17 exhibited an inhibitory effect on the gene expression of ALP, OCN, and Runx-2. The ALP activity and ALP mass of primary osteoblasts were downregulated by IL-17 treatment in a dose-dependent manner, and IL-17 failed to inhibit BMP-2-induced phosphorylation of Smad. CONCLUSION: Primary osteoblasts constitutively express IL-17 receptors, but none of C2C12 cells, MC3T3-E1 cells, and Saos-2 cells express any receptors for IL-17, IL-22, and IL-23. IL-17 inhibits BMP-2-induced osteoblast differentiation via the BMP/Smad-independent pathway.

Expression of cannabinoid receptor 2 and its inhibitory effects on synovial fibroblasts in rheumatoid arthritis.

OBJECTIVE: Recent studies have suggested immunomodulatory and anti-inflammatory effects of cannabinoid receptor 2 (CB2R) activation, which shows no psychoactivity. However, it is still unclear whether CB2R is expressed in fibroblast-like synoviocytes (FLS) of RA. In this study we investigated whether CB2R is expressed in FLS of RA, and whether CB2R activation modulates the function of RA-FLS. METHODS: Expression of CB2R in synovial tissue and FLS was studied by immunohistochemistry, western blotting and RT-PCR. mRNA expression levels of CB2R, IL-6 and MMPs were analysed by quantitative real-time RT-PCR. The protein concentrations of IL-6 and MMPs in culture supernatants were determined by ELISA. The protein levels of signal transducing molecules were assayed by western blotting. RESULTS: Both mRNA and protein expression of CB2R were found in synovial tissue and cultured FLS with slightly higher levels in RA patients than in OA patients. In cultured RA-FLS, the expression level of CB2R was up-regulated by stimulation with IL-1ß, TNF-α or lipopolysaccharide. In vitro, HU-308, a selective CB2R agonist, inhibited IL-1ß-induced proliferation of RA-FLS as well as IL-1ß-induced production of MMP-3, MMP-13 and IL-6 in RA-FLS in a dose-dependent manner. HU-308 also suppressed IL-1ß-induced activation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase in FLS. CONCLUSION: In RA-FLS, proinflammatory mediators up-regulate the expression of CB2R, which negatively regulates the production of proinflammatory cytokines and MMPs. These data suggest that CB2R may be a potential therapeutic target of RA.

Deubiquitination of aryl hydrocarbon receptor (AhR) by USP21 negatively regulates Th17 cells differentiation.

Aryl hydrocarbon receptor (AhR) is a key transcription factor that modulates the differentiation of T helper 17 (Th17) cells. How AhR is regulated at the post-translational level in Th17 cells remains largely unclear. Here we identify USP21 as a newly defined deubiquitinase of AhR. We demonstrate that USP21 interacts with and stabilizes AhR by removing the K48-linked polyubiquitin chains from AhR. Interestingly, USP21 inhibits the transcriptional activity of AhR in a deubiquitinating-dependent manner. USP21 deubiquitinates AhR at the K432 residue, and the maintenance of ubiquitination on this site is required for the intact transcriptional activity of AhR. Moreover, the deficiency of USP21 promotes the differentiation of Th17 cells both in vitro and in vivo. Consistently, adoptive transfer of USP21 deficient naïve CD4+ T cells elicits more severe colitis in Rag1-/- recipients. Therefore, our study reveals a novel mechanism in which USP21 deubiquitinates AhR and negatively regulates the differentiation of Th17 cells.

Intra-muscular arteries are also affected in Takayasu's arteritis.

Takayasu's arteritis (TA) is a chronic vasculitis, primarily affecting large vessels, such as the aorta and its main branches. Several reports suggest that the vascular inflammatory process is not always confined to large vessels. Here, a new case of vasculitis in intra-muscular arteries associated with TA is reported. This case provides further support for the idea that TA also involves small arterial vessels.

Cannabinoid receptor 2 protects against acute experimental sepsis in mice.

The systemic inflammatory response syndrome can be self-limited or can progress to severe sepsis and septic shock. Despite significant advances in the understanding of the molecular and cellular mechanisms of septic shock, it is still one of the most frequent and serious problems confronting clinicians in the treatments. And the effects of cannabinoid receptor 2 (CB2R) on the sepsis still remain undefined. The present study was aimed to explore the role and mechanism of CB2R in acute sepsis model of mice. Here, we found that mice were more vulnerable for lipopolysaccharide- (LPS-) induced death and inflammation after CB2R deletion (CB2R(-/-)). CB2R agonist, GW405833, could significantly extend the survival rate and decrease serum proinflammatory cytokines in LPS-treated mice. GW405833 dose-dependently inhibits proinflammatory cytokines release in splenocytes and peritoneal macrophages as well as splenocytes proliferation, and these effects were partly abolished in CB2R(-/-) splenocytes but completely abolished in CB2R(-/-) peritoneal macrophages. Further studies showed that GW405833 inhibits LPS-induced phosphorylation of ERK1/2 and STAT3 and blocks I κ B α degradation and NF- κB p65 nuclear translocation in macrophages. All data together showed that CB2R provides a protection and is a potential therapeutic target for the sepsis.

HMGB1 acts in synergy with lipopolysaccharide in activating rheumatoid synovial fibroblasts via p38 MAPK and NF-κB signaling pathways.

Synovial fibroblasts (SF) play a central role in the inflammatory and destructive process in rheumatoid arthritis (RA). High-mobility group box chromosomal protein 1 (HMGB1) or lipopolysaccharide (LPS) alone failed to induce significant changes in proliferation of cultured SF from RA patients, but premixed HMGB1 with LPS (HMGB1-LPS) significantly facilitated SF proliferation. HMGB1 alone failed to induce IL-6, MMP-3, and MMP-13 production in cultured SF but greatly enhanced LPS-induced expression of IL-6, MMP-3, and MMP-13 at both mRNA and protein levels. HMGB1-LPS synergistically upregulated TLR4 and receptor for advanced glycation endproducts (RAGE) expression on the surface of SF. Both blockers of TLR4 and RAGE significantly inhibited the synergistic effects of HMGB1-LPS on the production of IL-6 and MMPs, but blocking antibodies to TLR2 failed. HMGB1-LPS synergistically increased intracellular levels of phosphorylated p38 and phosphorylated I κ B. Furthermore, both NF- κ B inhibitor Bay11-7085 and p38 inhibitor SB203580 significantly suppressed the enhanced production of IL-6 and MMPs induced by HMGB1-LPS. In conclusion, HMGB1 acts in synergy with LPS to upregulate TLR4 and RAGE expression on the surface of SF in RA and then to augment IL-6, MMP-3, and MMP-13 production, which depends on p38 MAPK and NF-κB activation.

An interaction between the inflammatory condition and the hypercoagulable condition occurs in primary Sjögren syndrome.

This study aimed to assess the D-dimer level in patients with primary Sjögren syndrome (pSS), uncover its relationship with clinical symptoms, and appraise its predictive value in discriminating disease activity. The laboratory parameters of 101 consecutive patients with pSS and 101 healthy controls were analyzed and compared. Patients were divided into two subgroups according to their D-dimer levels, for the comparison of clinical features. Pearson's correlations were used to measure the relationships between D-dimer levels and other variables. The area under the curve (AUC) was calculated to predict disease activity. The erythrocyte sedimentation rate (ESR), high-sensitivity C-reactive protein (hsCRP) level, and D-dimer level were each higher in patients with pSS than in healthy controls. Compared with the low-D-dimer-level patients, those with elevated D-dimer levels exhibited higher ESRs (p < 0.0001) and higher levels of hsCRP (p < 0.0001), fibrinogen (p < 0.0001), and immunoglobulin A (p = 0.002). Cases with elevated D-dimer levels were prone to be more severe, based on ESSDAI evaluation (p < 0.0001). Patients with higher D-dimer levels had more articular involvement (p < 0.0001), which was significantly correlated with both the ESR (r = 0.21, p = 0.03) and hsCRP level (r = 0.56, p = 0.001). The D-dimer level may help to discriminate low disease activity from moderate/high disease activity (AUC = 0.754). The D-dimer level was correlated positively with both the ESR and hsCRP level in patients with pSS. The ESR and levels of hsCRP, fibrinogen, and disease activity were higher in the elevated D-dimer level group. The D-dimer level was demonstrated to have predictive value in differentiating pSS disease activity. Key Points •D-Dimer was higher in patients with pSS. •D-Dimer may help for predicting the disease activity in patients with pSS.

Platelet to albumin ratio is an independent indicator for disease activity in ankylosing spondylitis.

The objective of this study is to characterize the association between platelet to albumin ratio (PAR) and disease activity in patients with ankylosing spondylitis (AS) and axial psoriatic arthritis (axPsA). Baseline platelet count, albumin, PAR, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), Bath ankylosing spondylitis disease index (BASDAI), Bath ankylosing spondylitis functional index (BASFI), and ankylosing spondylitis disease activity score (ASDAS) were collected from patients with a definitive diagnosis of AS or axPsA. Spearman's correlation analysis, quantile regression, and receiver operating characteristic (ROC) curves were performed. Four hundred forty-six patients with AS and 68 patients with axPsA were included. AS patients had higher CRP, ASDAS-CRP, and ASDAS-ESR than axPsA patients (median: CRP, 6.8 vs. 3.5 mg/L, p = 0.02; ASDAS-CRP, 2.32 vs.1.93, p = 0.001; ASDAS-ESR, 2.57 vs.1.97, p = 0.007; respectively). Platelet count, albumin, PAR, ESR, BASDAI, and BASFI did not significantly differ between the two populations (all p > 0.05). In AS patients, PAR was positively correlated with BASDAI (r = 0.204, p < 0.01), BASFI (r = 0.24, p < 0.01), ASDAS-CRP (r = 0.475, p < 0.01), and ASDAS-ESR (r = 0.483, p < 0.01), while these coefficients were not significant in axPsA patients. The quantile regression further confirmed that, in AS patients, PAR was independently associated with BASDAI, BASFI, ASDAS-CRP, and ASDAS-ESR at their individual quantiles (all p < 0.01). However, in axPsA patients, PAR was not significantly associated with these disease activities. The optimal cut-off value of PAR for AS disease activity was 5.87, with an AUC of 0.745, a sensitivity of 72.4%, and a specificity of 71%. PAR could serve as an alternative indicator for AS disease activity. Key Points • Platelet to albumin ratio is independently associated with ankylosing spondylitis disease activity. • Platelet to albumin ratio could serve as an alternative indicator for ankylosing spondylitis disease activity.