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Ku70, a DNA repair protein, binds to the damaged DNA ends and orchestrates the recruitment of other proteins to facilitate repair of DNA double-strand breaks. Besides its essential role in DNA repair, several studies have highlighted non-classical functions of Ku70 in cellular processes. However, its function in immune homeostasis and anti-tumor immunity remains unknown. Here, we discovered a marked association between elevated Ku70 expression and unfavorable prognosis in lung adenocarcinoma, focusing specifically on increased Ku70 levels in tumor-infiltrated Treg cells. Using a lung-colonizing tumor model of in mice with Treg-specific Ku70 deficiency, we demonstrated that deletion of Ku70 in Treg cells led to a stronger anti-tumor response and slower tumor growth due to impaired immune-suppressive capacity of Treg cells. Furthermore, we confirmed that Ku70 played a critical role in sustaining the suppressive function of human Treg cells. We found that Ku70 bound to FOXP3 and occupied FOXP3-bound genomic sites to support its transcriptional activities. These findings not only unveil a non-homologous end joining (NHEJ)-independent role of Ku70 crucial for Treg suppressive function, but also underscore the potential of targeting Ku70 as an effective strategy in cancer therapy, aiming to both restrain cancer cells and enhance pulmonary anti-tumor immunity.

Introduction: The most common anatomic sites affected by extrapulmonary tuberculosis are lymph nodes, pleura, bones, and joints, urogenital tract, and meninges. Tuberculous arthritis is difficult to diagnose early because of its atypical insidious clinical manifestations and non-specific imaging findings., Case Report: A 59-year-old male presented with progressive swelling in his left knee for over two months. The patient was initially misdiagnosed with pigmented villonodular synovitis (PVNS) and had undergone total knee arthroplasty (TKA) two years ago, however, the TKA did not completely alleviate his symptoms. Comprehensive radiological and laboratory assessments, including X-rays, magnetic resonance imaging and computed tomography scans, and an interferon-γ release assay (IGRA), pointed towards a diagnosis of tuberculous knee arthritis. Definitive diagnosis was established through the detection of Mycobacterium tuberculosis (MTB) DNA in the synovial fluid via polymerase chain reaction (PCR) and a positive IGRA result., Conclusions: The case underscores the importance of considering MTB infection in the differential diagnosis of chronic unilateral knee arthritis, especially given the atypical clinical manifestations and imaging findings that can mimic other conditions like PVNS., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2024 Ran Cui, Qing Huang, Sheng-Ming Dai.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

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., Competing Interests: Declaration of competing interest B.L. is a cofounder of Biotheus Inc. and chairman of its scientific advisory board. The other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Reports on the prevalence of psoriatic arthritis (PsA) among Chinese patients with psoriasis are very limited. This study, conducted by rheumatologists, estimated the prevalence of PsA in a large number of Chinese patients with psoriasis., Methods: Consecutive patients with a confirmed diagnosis of psoriasis attending nine dermatology clinics in five hospitals were recruited. All psoriasis patients were asked to complete a questionnaire comprising 16 questions to identify possible cases of PsA. All patients with one or more positive answers to the questionnaire were evaluated by two experienced rheumatologists., Results: A total of 2434 psoriasis patients, including 1561 males and 873 females, were enrolled. Both the questionnaire and rheumatologists' examinations were completed in the dermatology clinics. The results identified 252 patients with PsA, comprising 168 males and 84 females. The overall prevalence of PsA among psoriasis patients was 10.4% (95% confidence interval [95% CI], 9.1%-11.7%). By sex, the prevalence was 10.8% (95% CI, 9.2%-12.5%) for males and 9.6% (95% CI, 7.7%-11.9%) for females and there was no significant sex difference in the prevalence of PsA (P = 0.38). Of the 252 PsA patients, 125 (49.6%, 95% CI, 41.3%-59.1%) were newly diagnosed by rheumatologists. Consequently, the prevalence of undiagnosed PsA among psoriasis patients was 5.2% (95% CI, 4.4%-6.2%)., Conclusion: The prevalence of PsA in the Chinese population with psoriasis is about 10.4%, which is almost double that of previous reports in the Chinese population, but lower than that in Caucasians., (Copyright © 2023 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Current evidence suggests that IL-23, IL-6, and TNF-α play pivotal roles in the pathogenesis of psoriasis. Although it has been established that Sirtuin 3 (SIRT3) mediates the inflammatory process, the underlying mechanisms remain largely unclear. Herein, we substantiated that the inhibition or deletion of SIRT3 increased the acetylation level of spliced form of X-box binding protein 1 (XPB1s), enhancing its transcriptional activity and IL-23a production. Pharmacologically inhibition of XBP1s with MKC8866 downregulated the expression of inflammatory cytokines in SIRT3-inhibited or Sirt3 -KO BMDMs stimulated by IMQ. Inhibition or knockdown of SIRT3 could exacerbate psoriasis-like skin inflammation in an imiquimod-induced psoriasis-like mouse model. Besides, a decrease in SIRT3 expression was observed in the macrophages of psoriasis patients, which increased the expression and acetylation level of XBP1s. Overall, we provide compelling evidence of the crucial role of SIRT3 in the IL-23 axis in psoriatic inflammation and novel molecular insights into the anti-inflammatory effects of SIRT3., 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 © 2023 Guo, Zhuang, Su, Meng, Liu, Liu, Wei, Dai and Deng.)

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.

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., (© 2023. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Background: Rheumatoid arthritis (RA), a chronic systemic autoimmune disease, is characterized by synovitis and progressive damage to the bone and cartilage of the joints, leading to disability and reduced quality of life. This study was a randomized clinical trial comparing the outcomes between withdrawal and dose reduction of tofacitinib in patients with RA who achieved sustained disease control., Methods: The study was designed as a multicenter, open-label, randomized controlled trial. Eligible patients who were taking tofacitinib (5 mg twice daily) and had achieved sustained RA remission or low disease activity (disease activity score in 28 joints [DAS28] ≤3.2) for at least 3 months were enrolled at six centers in Shanghai, China. Patients were randomly assigned (1:1:1) to one of three treatment groups: continuation of tofacitinib (5 mg twice daily); reduction in tofacitinib dose (5 mg daily); and withdrawal of tofacitinib. Efficacy and safety were assessed up to 6 months., Results: Overall, 122 eligible patients were enrolled, with 41 in the continuation group, 42 in the dose-reduction group, and 39 in the withdrawal group. After 6 months, the percentage of patients with a DAS28-erythrocyte sedimentation rate (ESR) of <3.2 was significantly lower in the withdrawal group than that in the reduction and continuation groups (20.5%, 64.3%, and 95.1%, respectively; P  < 0.0001 for both comparisons). The average flare-free time was 5.8 months for the continuation group, 4.7 months for the dose reduction group, and 2.4 months for the withdrawal group., Conclusion: Withdrawal of tofacitinib in patients with RA with stable disease control resulted in a rapid and significant loss of efficacy, while standard or reduced doses of tofacitinib maintained a favorable state., Trial Registration: Chictr.org, ChiCTR2000039799., (Copyright © 2023 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

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., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Objective: To evaluate and compare the risk of erectile dysfunction (ED) associated with the use of allopurinol and febuxostat in adult male gout patients., Methods: We conducted a cohort study using TriNetX (Cambridge, MA, USA), a global federated health research network that provides real-time electronic medical record datasets. We analyzed and compared the associated risk of ED in gout patients who started taking allopurinol or febuxostat within 12 months. Propensity score matching was performed to adjust for demographic variables, comorbidities, and medication use. Kaplan-Meier analysis was used to estimate the probability of the outcome of interest. The hazard ratio (HR) and associated confidence intervals were calculated along with the proportionality test using R's Survival Package v3.2-3., Results: We identified 679,862 patients with gout among 107,517,445 patients in the database. Of these patients, 24,000 were treated with febuxostat and 299,726 with allopurinol. After propensity matching, 9075 patients receiving febuxostat without allopurinol (febuxostat group) and 9075 corresponding patients receiving allopurinol without febuxostat (allopurinol group) were analyzed for comparison. Among all male patients over 19 years of age, febuxostat was associated with a significantly higher risk of ED versus allopurinol (HR 1.354; 95% confidence interval (CI) 1.003-1.829; log rank test, p = 0.047). After subgroup analysis, in gout patients aged 19-64 years, a significantly higher incidence of ED was observed in the febuxostat group than in the allopurinol group (HR 2.002, 95% CI 1.282-3.126). The risk of ED did not differ significantly between the allopurinol and febuxostat groups in gout patients older than 65 years., Conclusions: Febuxostat may be associated with a higher risk of ED than allopurinol in adult male patients with gout. Future large-scale prospective studies are warranted to confirm our results., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Psoriatic arthritis (PsA) without skin lesions is frequently confused with seronegative rheumatoid arthritis (RA). In this study, we aimed to promote diagnostic accuracy. Five PsA patients with no skin lesions were reviewed. We analyzed the clinical characteristics of these patients. All patients had multiple peripheral arthritis as well as axial involvement, and had been misdiagnosed with RA for several years initially. They developed severe deformation as a result of delayed diagnosis and inadequate treatment. Four patients had nail changes and one had a family history of psoriasis. They had hallmarks of PsA such as dactylitis, enthesitis, and distal interphalangeal arthritis. Ultrasound detection frequently revealed inflammation in the enthesis and extra-synovial areas. Nail psoriasis, dactylitis, enthesitis, distal interphalangeal arthritis, and extra-synovial inflammation would help to differentiate PsA from seronegative RA., (© 2022 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: The upregulation of interferon (IFN)-stimulated genes induced by type I IFNs (namely type I IFN signature) in rheumatoid arthritis (RA) patients had implications in early diagnosis and prediction of therapy responses. However, factors that modulate the type I IFN signature in RA are largely unknown. In this study, we aim to explore the involvement of VGLL3, a homologue of the vestigial-like gene in Drosophila and a putative regulator of the Hippo pathway, in the modulation of type I IFN signature in the fibroblast-like synoviocytes (FLS) of RA patients., Methods: FLS were isolated from RA and osteoarthritis (OA) patients. Expression of VGLL3 in the synovial tissues and FLS was analyzed by immunohistochemistry and PCR. RNA sequencing was performed in RA-FLS upon VGLL3 overexpression. The expression of IFN-stimulated genes was examined by PCR and Western blotting., Results: VGLL3 was upregulated in the RA synovium and RA-FLS compared to OA. Overexpression of VGLL3 promoted the expression of IFN-stimulated genes in RA-FLS. The expression of STAT1 and MX1 was also upregulated in RA synovium compared to OA and was associated with the expression of VGLL3 in RA and OA patients. VGLL3 promoted the IRF3 activation and IFN-β1 expression in RA-FLS. Increased IFN-β1 induced the expression of IFN-stimulated genes in RA-FLS in an autocrine manner. VGLL3 also modulated the expression of the Hippo pathway molecules WWTR1 and AMOTL2, which mediated the regulation of IRF3 activation and IFN-β1 production by VGLL3 in RA-FLS., Conclusions: VGLL3 drives the IRF3-induced IFN-β1 expression in RA-FLS by inhibiting WWTR1 expression and subsequently promotes the type I IFN signature expression in RA-FLS through autocrine IFN-β1 signaling., (© 2022. The Author(s).)

Nail disease in psoriasis has been found to be associated with psoriatic arthritis (PsA); however, which subtype of nail disease holds greater relevance to PsA remains unclear. This study was performed to explore the associations between three subtypes of fingernail disease (pitting, onycholysis, and hyperkeratosis) and PsA among patients with psoriasis. Patients with psoriasis attending five dermatology clinics in Shanghai between January 2020 and May 2021 were examined for skin, joint, and fingernail changes. Multivariate logistic regression analyses were utilized to test the strength of associations between subtypes of fingernail disease and PsA. The receiver operator characteristic (ROC) curve with area under curve (AUC) was used to evaluate their accuracies in diagnosing PsA. Sensitivity and specificity were also calculated. Of 1985 patients with psoriasis included, 228 (11.5%) patients were diagnosed with PsA, and the remaining patients were cutaneous-only psoriasis (PsC). One-hundred and fifty-seven (68.9%) patients with PsA and 748 (42.6%) patients with PsC had fingernail disease. Adjusted models showed that onycholysis and hyperkeratosis were the only type of fingernail disease independently associated with PsA. This association was further confirmed by the forward conditional stepwise regression model (OR, 95% CI for onycholysis: 2.34, 1.79 to 4.27, p < 0.01; for hyperkeratosis: 1.62, 1.12 to 2.66, p = 0.037). ROC analysis showed that, compared to pitting and hyperkeratosis, onycholysis had higher AUC (0.630) and sensitivity (52.6%). The psoriatic fingernail onycholysis and hyperkeratosis hold greater relevance to PsA than pitting. Clinically, psoriatic patients with fingernail onycholysis and hyperkeratosis should be assessed for arthritis. Key Points • Psoriatic fingernail onycholysis and hyperkeratosis, rather than pitting, are significantly associated with PsA • Clinically, psoriatic patients with fingernail onycholysis and hyperkeratosis should be assessed for arthritis., (© 2022. International League of Associations for Rheumatology (ILAR).)

Several screening tools have been developed to facilitate early diagnosis of psoriatic arthritis (PsA); however, their performance varied greatly across different studies. In this study, we validated and compared the performance of four screening tools in detecting undiagnosed PsA Chinese patients with psoriasis, and determined the key questions and their weights. The four screening tools were the Early Arthritis for Psoriatic Patients (EARP) questionnaire, Psoriatic Arthritis Screening and Evaluation (PASE) questionnaire, Psoriasis and Arthritis Screening Questionnaire (PASQ), and Psoriasis Epidemiology Screening Tool (PEST). The receiver-operator curve (ROC) with area under curve (AUC) was used to determine sensitivity, specificity, and accuracy. Least absolute shrinkage and selection operator and logistic regression were utilized to retrieve key questions, and a nomogram was utilized to visualize their weights. Of 482 psoriasis patients from dermatology clinics, 77 were newly diagnosed with PsA. Another 68 patients with newly diagnosed PsA from rheumatology clinics were incorporated in the analysis. ROC analysis indicated that the optimal cut-off values for EARP, PASE, PASQ, and PEST were 3, 40, 7, and 3, with corresponding sensitivities of 91.4%, 88.6%, 86.2%, and 88.5%, and specificities of 88.6%, 75.2%, 80.2%, and 83.6%, respectively. The AUC of EARP (0.925) was higher than those of PASE (0.885), PASQ (0.905), and PEST (0.827). However, none of them were sufficiently sensitive to identify pure axial PsA (sensitivities of EARP, PASQ, and PASE were 25.0%, 36.8%, and 42.1%, respectively). Twelve key questions were retrieved from these four tools to establish a nomogram with a high discrimination (C-index = 0.993) and a good calibration (mean absolute error = 0.014). In conclusion, to screen undiagnosed PsA, EARP has slightly better balanced sensitivity and specificity, and higher accuracy. The retrieval of key questions and nomogram signify the necessity of attributing different scores to differently weighted questions when developing a new screening tool to make it function more efficiently., (© 2022 Japanese Dermatological Association.)

Axial spondyloarthritis (axSpA) is comprised of ankylosing spondylitis (AS) and non-radiographic axSpA. In recent years, the involvement of the interleukin (IL)-23/IL-17 axis in the pathophysiology of axSpA has been widely proposed. Since IL-23 is an upstream activating cytokine of IL-17, theoretically targeting IL-23 should be effective in axSpA, especially after the success of the treatment with IL-17 blockers in the disorder. Unfortunately, IL-23 blockade did not show meaningful efficacy in clinical trials of AS. In this review, we analyzed the possible causes of the failure of IL-23 blockers in AS: 1) the available data from an animal model is not able to support that IL-23 is involved in a preclinical rather than clinical phase of axSpA; 2) Th17 cells are not principal inflammatory cells in the pathogenesis of axSpA; 3) IL-17 may be produced independently of IL-23 in several immune cell types other than Th17 cells in axSpA; 4) no solid evidence supports IL-23 as a pathogenic factor to induce enthesitis and bone formation. Taken together, IL-23 is not a principal proinflammatory cytokine in the pathogenesis of axSpA., 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 © 2022 Zhang, Jiang and Dai.)

Introduction: SLE is a chronic inflammatory systemic autoimmune disease with relapsing-remitting pattern. B-lymphocyte stimulator was involved in the pathogenesis of SLE. The humanised monoclonal antibody belimumab with 10 mg/kg was effective for active patients. However, the efficacy of low-dose belimumab for prevention of disease flares in patients with SLE with low disease activity is to be explored., Methods and Analysis: This is a multicentre, randomised, double-blind, placebo-controlled clinical trial. Patients who have Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) scores no higher than 6; with no A score or no more than one B score on the British Isles Lupus Assessment Group (BILAG) scale; and who are treated with prednisone (≤20 mg per day) at screening will be enrolled. 334 adults will be randomly assigned in a 1:1 ratio to receive intravenous 120 mg belimumab or placebo (saline) arm on weeks 0, 2, and 4, and then every 4 weeks until 48 weeks, with standard of care. The primary outcome measure is a composite index of severe or mild-to-moderate disease flares (SELENA-SLEDAI Flare Index) within 52 weeks. Secondary outcomes include the percentage of severe flare, the percentage of mild-to-moderate flare, time to first disease flare, changes in prednisone dose, SELENA-SLEDAI, as well as BILAG score, the percentage of patients achieving prednisone free and safety analysis., Ethics and Dissemination: The protocol has been approved by the Ethics Committee of the Renji Hospital, Huashan Hospital and the Sixth People's Hospital. The trial has been registered and the detailed information is available at https://clinicaltrialsgov/ct2/show/NCT04515719. The results of this clinical trial will be submitted for publication in peer-reviewed journals and key findings will also be presented at national and international conferences., Trial Registration Number: NCT04515719., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: High prevalence of undiagnosed psoriatic arthritis (PsA) and prolonged diagnostic delay are key troubles in the appropriate management of PsA. To analyze the possible causes for this phenomenon, a web-based nationwide survey was conducted to investigate rheumatologists' perceptions on PsA diagnosis in China., Methods: The electronic questionnaire consisting of 38 questions were designed by an expert panel and distributed with the online survey tool Sojump, which is a professional online survey platform. The completed questionnaires by real-name rheumatologists were collected., Results: A total of 1594 valid questionnaires were included. More than half of Chinese rheumatologists reported it was challenging to make a diagnosis of PsA. The four major challenges were "Difficulties in identification of atypical or hidden psoriasis", "Absence of diagnostic biomarkers", "No active self-report of history or family history of psoriasis" and "Various musculoskeletal manifestations". In diagnosing PsA, minor participants had incorrect knowledge of inflammatory arthropathy (13.7%), acute phase reactant (23.8%), and rheumatoid factor (28.7%). There were no significant differences in the knowledge of PsA and practice habits in diagnosing PsA between modern western medicine (WM)- and traditional Chinese medicine (TCM)-rheumatologists. The part-time rheumatologists were not as good as full-time rheumatologists in diagnosing PsA., Conclusions: About three quarters of Chinese rheumatologists are familiar with the elements in PsA diagnosis and have good practice habits in diagnosing PsA. Four main challenges in making PsA diagnosis are revealed. There was no significant difference in the knowledge of PsA between WM- and TCM-rheumatologists., 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 © 2021 Chen, Zhang, Chen and Dai.)

Background: Takayasu arteritis (TAK) is a rare large vessel vasculitis, and epidemiological data on TAK are lacking in China. Thus, we designed this study to estimate the TAK prevalence and incidence in residential Shanghai, China., Methods: Data on diagnosed TAK cases aged over 16 years were retrieved from 22 tertiary hospitals in Shanghai through hospital electronic medical record systems between January 1, 2015 and December 31, 2017 to estimate the prevalence and incidence. A systematic literature review based on searches in PubMed, Ovid-Medline, Excerpta Medica Database (EMBASE), Web of Science, and China National Knowledge Infrastructure (CNKI) was performed to summarize TAK distribution across the world., Results: In total 102 TAK patients, with 64% female, were identified. The point prevalence (2015-2017) was 7.01 (95% CI 5.65-8.37) cases per million, and the mean annual incidence was 2.33 (1.97-3.21) cases per million. The average age of TAK patients was 44 ± 16 years, with the highest prevalence (11.59 [9.23-19.50] cases per million) and incidence (3.55 [0.72 3.74] cases per million) in the 16 to 34 years population. Seventeen reports were included in the system review, showing that the epidemiology of TAK varied greatly across the world. The incidence and prevalence were both relatively higher in Asian countries, with the prevalence ranging 3.3-40 cases per million and annual incidence ranging 0.34-2.4 cases per million., Conclusions: The prevalence and incidence of TAK in Shanghai was at moderate to high levels among the previous reports. The disease burden varied globally among racial populations., (© 2021 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objective: Patients with psoriasis (PsO) have a high frequency of concomitant gout and increased risk of cardiovascular diseases (CVD). We aimed to estimate the synergistic impact of gout on the risk of CVD in patients with PsO., Methods: A population-based cohort of patients registered in the National Health Insurance Research Database of Taiwan between 2000 and 2013 was stratified according to the presence of PsO and gout. Propensity score analysis was used to match age and gender at a ratio of 1:4. Cox proportional hazard models and subgroup analyses were used to estimate the hazard ratios (HRs) for CVD adjusted for traditional risk factors. The Kaplan-Meier method was used to plot the cumulative incidence curves., Results: Patients with combined PsO and gout (n = 97), PsO alone (n = 388), gout alone (matched, n = 388) and matched controls (n = 388) were identified. Compared with the patients with PsO alone, the patients with combined PsO and gout had a significantly higher risk of CVD (relative risk 2.39, 95% CI 1.56 to 3.65). After adjustment for traditional risk factors, the risk of CVD was higher in patients with gout alone (HR 2.16, 95% CI 1.54 to 3.04) and in patients with combined PsO and gout (HR 2.72, 95% CI 1.73 to 4.28)., Conclusions: Gout augments the risk of CVD independently of traditional risk factors in patients with PsO., 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 © 2021 Chen, Xu, Chen, Cui, Wang, Dai and Wei.)

Fibroblast-like synoviocytes (FLS) in the synovial tissue of rheumatoid arthritis (RA) exhibit over-proliferative and aggressive phenotypes, which participate in the pathophysiology of RA. In RA, little is known about the nonantioxidant effect of nuclear factor erythroid 2-related factor 2 (nrf2), the master regulator of redox homeostasis. In this study, we aimed to explore the expression and upstream regulatory factors of nrf2 and revealed its functions in modulating the proliferation and invasion in RA-FLS. FLS were isolated from RA and osteoarthritis patients. Expression of nrf2 in the synovial tissues and FLS was analyzed by immunohistochemistry, real-time PCR, Western blotting, and immunofluorescence staining. Cell proliferation was examined by Cell Counting Kit-8. Cell invasion was tested by transwell assay. Phosphorylation of JNK was determined by Western blotting. The results showed that nrf2 expression in the RA synovial tissues was upregulated. TNF- α promoted expression and nuclear translocation of nrf2 in RA-FLS and increased the intracellular reactive oxygen species (ROS) level. Nrf2 nuclear translocation was blocked by ROS inhibitor N-acetylcysteine. Both knockdown of nrf2 by siRNA and inhibition of nrf2 by ML385 significantly promoted the TNF- α -induced proliferation and invasion of RA-FLS. Activation of nrf2 by sulforaphane (SFN) profoundly inhibited the TNF- α -induced proliferation and invasion of RA-FLS. Knockdown of nrf2 also enhanced the TNF- α -induced matrix metalloproteinases (MMPs) expression and phosphorylation of JNK in RA-FLS. Proliferation and invasion of RA-FLS incubated with TNF- α and nrf2 siRNA were inhibited by pretreatment with JNK inhibitor SP600125. In conclusion, nrf2 is overexpressed in synovial tissues of RA patients, which may be promoted by TNF- α and ROS levels. Activation of nrf2 may suppress TNF- α -induced proliferation, invasion, and MMPs expression in RA-FLS by inhibiting JNK activation, indicating that nrf2 plays a protective role in relieving the severity of synovitis in RA. Our results might provide novel insights into the treatment of RA., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 Yu Du et al.)

Sjögren's syndrome (SS) is a common systemic autoimmune disease. SS usually occurs among middle-aged women with a peak incidence age of approximately 50 years old. Kidney involvement is relatively uncommon in SS, which is mostly characterized as interstitial nephritis and may result in renal tubular acidosis (RTA). But premature onset of SS seems to be prone to RTA. Here we reported four cases of premature onset SS who developed into RTA at a relatively young age and three of whom suffered from severe osteomalacia. All of them shared a disease onset under age eighteen. Two of them presented hypokalemic periodic paralysis initially, one presented purpura and one endured xerophthalmia at first place. Three of them complicated with osteomalacia under age thirty. All the 4 cases didn't receive proper medical care in time due to a prolonged delay of diagnosis. We aim to raise the alarm over misdiagnosis/underdiagnosis of the disorder among young people., (© 2020 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

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., (Copyright © 2020 by The American Association of Immunologists, Inc.)

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., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: This study aims to analyze the expression profile of osteoclasts (OCs) following the stimulation with interleukin 23 (IL-23) in mice, which would imply the underlying effects of IL-23 on the function of OCs in inflammatory arthritis., Materials and Methods: Mature OCs were induced from bone marrow mononuclear cells of 5 male mice (age 6 weeks; weighing 18-20 g) in the presence of macrophage-colony stimulating factor (50 ng/mL) and receptor activator of nuclear factor kappa B ligand (30 ng/mL) in vitro. The Agilent SurePrint G3 Mouse GE V2.0 Microarray was used to analyze the gene expression profile of OCs stimulated with IL-23 (30 ng/mL) or vehicle. The four major IL-23-modulated genes were validated by quantitative real-time polymerase chain reaction (qPCR) analysis., Results: The expression levels of 23 genes were up-regulated and 32 genes were down-regulated by IL-23 stimulation (fold change ≥1.5 and p value <0.05). Among them, there were 37 genes with assigned gene symbols. Gene ontology analysis showed that the IL-23-regulated messenger ribonucleic acids (mRNAs) were related to positive regulation of leukocyte chemotaxis, chemokine-mediated signaling pathway and C-X-C chemokine receptors binding. The pathway analysis showed that the IL-23-regulated mRNAs were related to chemokine signaling pathway and cytokine-cytokine receptor interaction. The significant up-regulation of chemokine (C-X-C motif) ligand 1 and chemokine (C-X-C motif) ligand 2 induced by IL-23 was confirmed by qPCR. In addition, there were 18 long non-coding RNAs that were regulated by IL-23, while their function needs to be confirmed in the future., Conclusion: Expression levels of genes related to chemotaxis in OCs were up-regulated by IL-23 in mice, which imply that IL-23 may facilitate chemotaxis of OCs in inflammatory arthritis., Competing Interests: Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article., (Copyright © 2020, Turkish League Against Rheumatism.)

Psoriatic arthritis (PsA) is a type of chronic inflammatory arthritis which is associated with psoriasis. The early recognition and treatment for PsA are of critical importance. Janus kinase (JAK) inhibitors, as a kind of orally small molecules, have emerged as an encouraging class of drug in PsA treatment. This review provides a discussion of the role and current status of JAK inhibitors in the control of PsA. There are three JAK inhibitors approved for use in autoimmune diseases, for example, tofacitinib, baricitinib, and upadacitinib, and only tofacitinib has been approved in PsA treatment. The clinical trials of upadacitinib and filgotinib in PsA patients are undergoing. The efficacy and safety of these agents were briefly discussed. Although there are still issues in terms of their efficacy and safety currently, JAK inhibitors are expected to benefit more PsA patients in future.

Objective: Despite extensive studies, the precise mechanism underlying spondyloarthritis, especially ankylosing spondylitis, remains elusive. This study aimed to develop an ideal animal model for an insight into mechanism of spondyloarthritis and functional relevance of SOCS3 in spondyloarthritis. Methods: Since SOCS3 is a major regulator of IL23-STAT3 signaling, we generated SOCS3 knockdown transgenic (TG) mice for development of an animal model of spondyloarthritis. A hydrodynamic delivery method was employed to deliver minicircle DNA expressing IL23 (mc-IL23) into wild-type (WT) and the TG mice. Knockdown/overexpression systems mediated by lentivirus and retrovirus were used to determine whether SOCS3 regulated osteoblast differentiation. Results: Forced expression of IL23 induced severe joint destruction and extensive bone loss in SOCS3 knockdown TG mice, while this treatment only caused moderate symptoms in WT mice. Furthermore, severe spondyloarthritis was found in IL23-injected TG mice as compared to mild disease observed in WT controls under same condition. Moreover, our studies showed that IL23 promoted osteoblast differentiation via activation of STAT3 pathway and disruption of SOCS3 expression greatly increased phosphorylation of STAT3. In addition, silencing SOCS3 resulted in enhanced osteoblast differentiation through activation of Smad1/5/9 signaling, as evidenced by elevated phosphorylation level of Smad1/5/9. Experiments further demonstrated that SOCS3 interacted with Smad1 and thus suppressed the BMP2-Smad signaling. Conclusions: The results reveal that SOCS3 is involved in IL23-induced spondyloarthritis and acts as a key regulator of osteoblast differentiation, and suggest that SOCS3 knockdown TG mice may be an ideal animal model for further studies of spondyloarthritis.

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.

The study aimed to determine whether unique clinical patterns of AS may exist in China, specifically to explore the different clinical manifestations caused by gender, HLA-B27 status, and age at disease onset. The multicenter cross-sectional survey was conducted and 1251 patients were enrolled across China, representing a broad spectrum of Chinese AS patients. The mean age at onset and diagnosis were 29.2 (11.4) and 33.5 (12.6) years, respectively. The male/female ratio was 2.7:1. Acute anterior uveitis (AAU) was experienced in 10.3% of AS patients and 9.1% patients had juvenile-onset AS (JoAS). Men were significantly younger at onset and diagnosis and showed a higher frequency of HLA-B27 positivity, JoAS, and AAU than women. HLA-B27-positive patients had a younger age of onset than HLA-B27-negative patients. HLA-B27-positive patients were nearly three times as likely to develop AAU than negative patients (P = 0.04). JoAS patients had a family history of AS more often than adult-onset AS (AoAS) patients, and 4.9% of JoAS patients underwent surgical treatments, a rate more than six times that of AoAS patients (P = 0.01). Men had higher levels of C-reactive protein than women, as did HLA-B27 positives compared to negative patients, and JoAS compared to AoAS (all P < 0.05). The clinical patterns of our AS patients were similar to those in other studies in non-Chinese cohort: (1) the age at onset was 29.2 (11.4) years, which was older than found in other studies; (2) men were more likely be HLA-B27 carriers than women; and (3) AAU was less common in Chinese patients.

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.

Objectives: To better understand the effect of TNF-α inhibitors (TNFi) on new bone formation in ankylosing spondylitis (AS) patients., Methods: We systematically searched the articles in EMBASE and PubMed., Results: Fifteen articles were enrolled. In all the 9 TNFi-treated cohorts, the vertebral corners with inflammatory lesions at baseline were at higher risk to develop new syndesmophytes than those without inflammatory lesions, although a few syndesmophytes also developed at the vertebral corners without inflammatory lesions at baseline. The advanced inflammatory lesions including fat deposition on baseline MRI showed a higher risk for syndesmophyte formation than the acute inflammatory lesions. Because the number of analyzed vertebral corners were too small, it might not be true that new syndesmophytes developed more frequently at the corners with inflammatory lesions completely resolved than those with persistent inflammation after TNFi treatment. Four studies with 2-year follow-up revealed null effect of TNFi on radiographic progression compared with historical controls with lower disease activity, and 3 studies with ≥4-year follow-up proved inhibitory effect of TNFi on new bone formation in AS patients. Patients with a delay of >10 years in starting TNFi therapy were more likely to experience radiographic progression as compared to those who started earlier., Conclusions: In TNFi treated AS patients, baseline inflammation is linked with syndesmophyte development. An earlier initiation of TNFi therapy may slow the radiographic progression in AS, and TNFi may lose its benefit of retarding new bone formation at advanced stage of AS especially after the focal fat infiltration or syndesmophyte formation., (Copyright © 2015 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Objectives: Recent studies have suggested immunomodulatory and anti-inflammatory effects of cannabinoid receptor 2 (CB2R) activation, which is devoid of psychoactivity. We have demonstrated the expression of CB2R in synovial tissue from patients with rheumatoid arthritis (RA), and its specific activation shows inhibitory effects on fibroblast-like synoviocytes. However, it is still unclear whether selective activation of CB2R inhibits joint inflammation or protects joint damage in RA., Methods: A murine model of collagen-induced arthritis (CIA) was used to evaluate the therapeutic efficacy of HU-308, a selective CB2R agonist. The disease severity was evaluated by semi-quantitative scoring of joint swelling, histological assessment of joint inflammation and structure, and radiographic assessment of joint destruction by using digital plain radiographs and micro-CT scans. The concentrations of various isotypes of anti-collagen II antibodies in sera and the levels of cytokines in culture supernatants were determined by ELISA., Results: Compared with vehicle treatment, protective treatment with intraperitoneal injection of HU-308 (0.3-1.0 mg/kg) failed to decrease the incidence of the development of CIA, but it effectively suppressed the severity of the disease. In CIA mice, treatment with HU-308 significantly decreased joint swelling, synovial inflammation, and joint destruction, as well as serum levels of anti-collagen II antibodies. In vitro, HU-308 (1-10 μM) significantly suppressed the production of proinflammatory cytokines IL-6 and TNF-α from lipopolysaccharide-stimulated murine peritoneal macrophages with intact CB2R in dose-dependent manners. HU-308 failed to elicit any inhibitory effect of on lipopolysaccharide-stimulated macrophages from CB2R-knockout mice., Conclusions: Activation of CB2R by HU-308 has therapeutic potential for RA to suppress synovitis and alleviate joint destruction by inhibiting the production of autoantibodies and proinflammatory cytokines., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Since the discovery of the endogenous receptor for Δ(9)-tetrahydrocannabinol, a main constituent of marijuana, the endocannabinoid system (comprising cannabinoid receptors and their endogenous ligands, as well as the enzymes involved in their metabolic processes) has been implicated as having multiple regulatory functions in many central and peripheral conditions, including rheumatoid arthritis (RA). RA is an immune-mediated inflammatory disease that is associated with the involvement of many kinds of cells (such as fibroblastlike synoviocytes [FLSs], osteoclasts, T cells, B cells, and macrophages) and molecules (such as interleukin-1β, tumor necrosis factor-α, interleukin-6, matrix metalloproteinases [MMPs], and chemokines). Increasing evidence suggests that the endocannabinoid system, especially cannabinoid receptor 2 (CB2), has an important role in the pathophysiology of RA. Many members of the endocannabinoid system are reported to inhibit synovial inflammation, hyperplasia, and cartilage destruction in RA. In particular, specific activation of CB2 may relieve RA by inhibiting not only the production of autoantibodies, proinflammatory cytokines, and MMPs, but also bone erosion, immune response mediated by T cells, and the proliferation of FLSs. In this review, we will discuss the possible functions of the endocannabinoid system in the modulation of RA, which may be a potential target for treatment., (Copyright © 2015 Elsevier B.V. All rights reserved.)

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-1β, TNF-α or lipopolysaccharide. In vitro, HU-308, a selective CB2R agonist, inhibited IL-1β-induced proliferation of RA-FLS as well as IL-1β-induced production of MMP-3, MMP-13 and IL-6 in RA-FLS in a dose-dependent manner. HU-308 also suppressed IL-1β-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.