Evaluation of early retinal changes in patients on long-term hydroxychloroquine using optical coherence tomography angiography.

Background: Connective tissue diseases (CTD), including systemic lupus erythematosus and rheumatoid arthritis (RA), have long been treated with hydroxychloroquine (HCQ). However, prolonged HCQ use poses a risk of adverse effects, particularly retinopathy. Objective: To detect early retinal changes assessed by optical coherence tomography angiography (OCTA) in CTD patients with long-term HCQ treatment and to explore the relationship between OCTA parameters and the concentrations of HCQ and its metabolites. Design: A cross-sectional study conducted from March 2020 to October 2021 at the First Affiliated Hospital of Anhui Medical University. Methods: The area and perimeter of the foveal avascular zone (FAZ), the thickness of the fovea and parafovea, and the vascular density of the superficial capillary plexus (SCP) and deep capillary plexus (DCP) in each area of the macula were measured by OCTA in 43 CTD patients treated with HCQ for over 6 months. Meantime, blood concentrations of HCQ and its metabolites were determined by high-performance liquid chromatography-tandem mass spectrometry, and the clinical documents of all 43 involved patients were collected. Results: There is no significant correlation between OCTA outcomes and the patient's age, disease duration, and weight-dependent dose. HCQ cumulative duration positively correlated with FAZ area and perimeter (r = 0.419, p = 0.005 and r = 0.407, p = 0.007, respectively) and negatively correlated with the foveal vessel density in DCP (r = -0.378, p = 0.012). HCQ cumulative dose had a positive correlation with FAZ area and perimeter (r = 0.445, p = 0.003 and r = 0.434, p = 0.004, respectively) and had a negative correlation with foveal vessel density in SCP and DCP (r = -0.383, p = 0.011 and r = -0.424, p = 0.005, respectively). OCTA outcomes did not correlate with HCQ and its metabolite concentrations. Conclusion: OCTA could be used to detect microvascular changes in the macula of CTD patients with long-term HCQ therapy. It was not found the concentrations of HCQ and its metabolites were associated with retinal vascular changes.

Aberrant DNA Methylation Profile of Dickkopf-1 in Ankylosing Spondylitis.

In recent years, the impact of methylation modifications on Dickkopf-1 (DKK1) in relation to ankylosing spondylitis (AS) has remained elusive. Our objective was to investigate the potential link between DKK1 methylation patterns and transcript levels and AS susceptibility. DNA methylation level of DKK1 was measured in 82 AS and 82 healthy controls (HCs) using targeted bisulfite sequencing. In addition, the transcript level of DKK1 in peripheral blood mononuclear cells from 35 AS patients and 35 HCs was detected using real-time quantitative transcription-polymerase chain reaction. Our study showed that the DKK1 was significantly hypomethylated in AS patients (P < 0.001). The Receiver operating characteristic curve (ROC) showed that DKK1 methylation may be a potential biomarker. The results showed that the difference in DKK1 transcript levels between AS and HCs was not statistically significant. Further analysis showed that DKK1 methylation levels were positively correlated with age and negatively correlated with C-reactive protein levels, neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR). The methylation level of DKK1 in PBMC of AS patients was significantly lower than that of HCs, and DKK1 methylation may be associated with susceptibility to AS. In addition, DNA methylation levels of DKK1 were negatively correlated with the level of inflammation in AS patients.

HSCs-derived exosomes regulate the levels of inflammatory cytokines in HIBECs through miR-122-5p mediated p38 MAPK signaling pathway.

PBC is an autoimmune-mediated liver disease, and intrahepatic biliary epithelial cells (IBECs) are the target cells of early damage. Previous studies found that miRNAs and inflammation is closely related to PBC. In this study, we extracted exosomes from serum and human IBECs supernatant, and RNA-sequence analyzed the expression profiles of miRNAs. Elisa measured the levels of inflammatory cytokines. RT- qPCR and western blot detected the levels of miR-122-5p, p38 and p-p38. The results showed that 263 differentially expressed (DE) miRNAs were identified in serum exosomes of PBC patients. The levels of IL-1ß, IL-6, IL-12, IL-17 A, IFN-γ, TNF-α and TGF-ß1 in peripheral blood of PBC patients were higher than those of normal controls. According to the validation results and previous literature, exosomal miR-122-5p was finally selected as the study object, and correlated with inflammatory factors. In vitro experiments further found that exosomal miR-122-5p may derive from hepatic stellate cells (HSCs), and can be HIBECs intake, and influence HIBECs inflammatory factor levels though p38 MAPK signaling pathways. This may provide a new strategy for the treatment of PBC.

The presumable effects of hydroxychloroquine and its metabolites in the treatment of systemic lupus erythematosus.

OBJECTIVE: Hydroxychloroquine (HCQ) is an essential drug in the treatment of systemic lupus erythematosus (SLE). This study aimed to detect the concentrations of HCQ and its metabolites from peripheral blood of SLE patients and to investigate the relationship between those concentrations and SLE disease activity. METHODS: 176 SLE patients treated with HCQ were enrolled in this study. The concentrations of HCQ and its metabolites in their peripheral blood were measured by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Patients' disease activity was evaluated with the systemic lupus erythematosus disease activity index (SLEDAI). The variables between different concentrations or treatments were statistically analyzed. Linear regression was employed to explore relationships between the concentrations of HCQ and its metabolites with the disease activity. RESULTS: The SLEDAI was lower in patients with higher concentrations of HCQ, desethylhydroxychloroquine (DHCQ), and desethylchloroquine (DCQ) (P = 0.024, P = 0.018, and P = 0.003, respectively). There were no significant differences in SLEDAI and the concentrations of HCQ and its metabolites among groups with different treatments (P > 0.05). After adjusting age, gender, disease duration, HCQ dose adjusted to actual body weight, and glucocorticoid (GC) dose, the SLEDAI was negatively correlated with the concentrations of HCQ, DHCQ, DCQ and bisdesethylchloroquine (BDCQ) (P = 0.007, P = 0.011, P = 0.029, and P = 0.008, respectively). After grouping analysis, in patients treated with HCQ and GC, the SLEDAI was negatively correlated with concentrations of HCQ, DHCQ and BDCQ (P = 0.011, P = 0.035, and P = 0.036, respectively). CONCLUSIONS: The concentrations of HCQ and metabolites were correlated with the SLE disease activity after adjusting possible confounding factors, indicating that HCQ and its metabolites might play certain immunoregulatory roles in SLE treatment. Moreover, GC might have a synergistic effect with HCQ. It is helpful in clinical management and follow-up to monitor the concentrations of HCQ and its metabolites in SLE patients.

Mir-142-3P regulates MAPK protein family by inhibiting 14-3-3η to enhance bone marrow mesenchymal stem cells osteogenesis.

Clinical studies have found 14-3-3η to be associated with osteoporosis through undefined mechanisms. We aimed to investigate the role of 14-3-3η in osteoporosis and its potential associations with miRNAs. The Gene Expression Omnibus(GEO) and Human Protein Atlas 1 databases were analyzed to examine both the mRNA and protein expression of 14-3-3η in OP. Gene enrichment analyses were performed to explore the underlying mechanism of 14-3-3η based on DAVID. miRWalk was used to predict the associated miRNAs. The statistics were analysed by R software and SPSS software. 14-3-3η was overexpressed and knock down expressed in BMSCs by lentiviral vector transfecting. And BMSCs were induced by hypoxia. qRT-PCR and Western-Blot verified the expression of mRNA and protein. Scratch assay detected the migration of osteocytes. Co-immunoprecipitation and luciferase assay studied the 14-3-3η targeted protein and miRNA. overexpression and knock down of miRNA to verify the relationship of 14-3-3η and target genes. The 14-3-3η mRNA expression level was low in patients with osteoporosis, as corroborated by immunohistochemical staining images. Functional analyses revealed enrichment of the MAPK-associated cascade. 14-3-3η was correlated with MAPK family proteins and five key miRNAs, including mir-142-3p. In addition, 14-3-3η knockdown in BMSCs increased the mRNA and protein expression levels of Hif-α, VEGF, BMP-2, OPN, OST, and Runx2, and enhanced the cells migration ability. Under hypoxic conditions, Hif-α and BMP-2 protein expression levels were upregulated, whereas those of 14-3-3η and MAPK3 were downregulated. Co-immunoprecipitation experiments showed decreased binding of 14-3-3η to MAPK3. 14-3-3η knockdown produced the same results as hypoxia induction. Adding caspase3 inhibitor and knocking down 14-3-3η again prevented MAPK3 cleavage by caspase3 and inhibited BMP-2 expression. Moreover, under hypoxic conditions, miR-142-3P expression was upregulated and luciferase assays revealed 14-3-3η as its target gene. miR-142-3P overexpression decreased mRNA and protein levels of 14-3-3η and MAPK3, while increasing BMP-2 expression. miR-142-3P knockdown reversed these results. BMSC osteogenesis was suppressed by 14-3-3η, whereas miRNA-142-3p promoted it through the inhibition of 14-3-3η.

Understanding the role of exosomal lncRNAs in rheumatic diseases: a review.

Rheumatic diseases, a group of diseases whose etiology is still unclear, are thought to be related to genetic and environmental factors, leading to complex pathogenesis. Based on their multi-system involvement, the diagnosis and treatment continue to face huge challenges. Whole-genome assays provide a distinct direction for understanding the underlying mechanisms of such diseases. Exosomes, nano-sized bilayer membrane vesicles secreted by cells, are mentioned as a key element in the physiological and pathological processes of the body. These exosomes mediate biologically active substances, such as nucleic acids, proteins, and lipids and deliver them to cells. Notably, long non-coding RNAs (lncRNAs), a unique class of non-coding RNAs, have been implicated in the pathogenesis of rheumatic diseases. However, the mechanism needs to be further explored. This article provided a comprehensive review of the findings on exosomal lncRNAs in rheumatic diseases, including rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, autoimmune liver diseases, primary dermatomyositis, and systemic sclerosis. Through in-depth understanding of these lncRNAs and their involved signaling pathways provide new theoretical supports for the diagnosis and treatment of rheumatic diseases.

METTL14-m6A-FOXO3a axis regulates autophagy and inflammation in ankylosing spondylitis.

The role of m6A in ankylosing spondylitis (AS) remains largely obscure. In this study, we found that m6A modification was decreased in T cells of AS, and the abnormal m6A modification was attributed to the downregulation of methyltransferase-like 14 (METTL14). METTL14 exerted a critical role in regulating autophagy activity and inflammation via targeting Forkhead box O3a (FOXO3a). Mechanistically, the loss of METTL14 decreased the expression of FOXO3a, leading to the damage of autophagic flux and the aggravation of inflammation. Inversely, the forced expression of METTL14 upregulated the expression of FOXO3a, thereby activating autophagy and alleviating inflammation. Furthermore, our results revealed that METTL14 targeted FOXO3a mRNA and regulated its expression and stability in a m6A-dependent manner. These findings uncovered the functional importance of m6A methylation mechanisms in the regulation of autophagy and inflammation, which expanded our understanding of this interaction and was critical for the development of therapeutic strategies for AS.

Differences of RUNX2 gene promoter methylation and transcription level in ankylosing spondylitis.

BACKGROUND AND OBJECTIVE: Ankylosing spondylitis is a refractory immune disease that seriously affects the life and work of patients. Epigenetic modifications, especially DNA methylation, have become a research hotspot in complex diseases. We aim to explore the changes in runt-related transcription factor 2 (RUNX2) gene promoter methylation and transcription level in AS. METHOD: We detected the RUNX2 gene promoter methylation in 83 AS patients and 83 healthy controls (HCs), then inspected the mRNA difference of RUNX2 between 30 AS patients and 30 HCs by the quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: The RUNX2 gene promoter was hypomethylated in AS patients compared to HCs (p < .001). The research involved 4 CpG regions and 74 CpG sites of RUNX2, of which CpG-2, CpG-4 regions, and 18 CpG sites have been differentially methylated. The CpG-4 island methylation was negatively correlated with C-reactive protein (p < .05) in AS patients. In the qRT-PCR validation phase, the mRNA level of RUNX2 in AS patients was significantly higher than HCs (p < .05), and in AS patients who were treated with biologics, the methylation level of CpG-2 island showed a negative correlation to mRNA (p < .05). ROC results indicated that RUNX2 methylation and its transcription level have good potential to distinguish AS patients from HCs. CONCLUSION: The RUNX2 gene promoter was hypomethylated in AS patients. Meanwhile, the qRT-PCR verified the up-regulated expression on the transcription level, suggesting the abnormal methylation of RUNX2 contributes to the pathogenesis of AS.

Differential Expression Profiles of Plasma Exosomal microRNAs in Rheumatoid Arthritis.

Aim: Differential expression maps of microRNAs (miRNAs) are connected to the autoimmune diseases. This study sought to elucidate the expression maps of exosomal miRNA in plasma of rheumatoid arthritis (RA) patients and their potential clinical significance. Methods: In the screening phase, small RNA sequencing was performed to characterize dysregulated exosome-derived miRNAs in the plasma samples from six patients with RA and six healthy patients. At the independent verification stage, the candidate plasma exosomal miRNAs were verified in 40 patients with RA and 32 healthy patients by using qRT-PCR. The correlation of miRNA levels and clinical characteristics was tested in patients with RA. The value of these miRNAs in diagnosing RA was assessed with the receiver operating characteristic curve. Results: During the screening phase, 177 and 129 miRNAs were increased and decreased in RA patients and healthy controls, respectively. There were 10 candidate plasma exosomal miRNAs selected for the next identification. Compared with the healthy controls, eight plasma exosomal miRNAs (let-7a-5p, let-7b-5p, let-7d-5p, let-7f-5p, let-7g-5p, let-7i-5p, miR-128-3p, and miR-25-3p) were significantly elevated in RA patients, but miR-144-3p and miR-15a-5p expression exhibited no significant changes. The let-7a-5p and miR-25-3p levels were linked to the rheumatoid factor-positive phenotype in RA patients. For the eight miRNAs, the area under the subject work characteristic curve (AUC) is 0.641 to 0.843, and their combination had a high diagnostic accuracy for RA (AUC = 0.916). Conclusion: Our study illustrates that novel exosomal miRNAs in the plasma may represent potential noninvasive biomarkers for RA.

The gut ecosystem and immune tolerance.

The gastrointestinal tract is home to the largest microbial population in the human body. The gut microbiota plays significant roles in the development of the gut immune system and has a substantial impact on the maintenance of immune tolerance beginning in early life. These microbes interact with the immune system in a dynamic and interdependent manner. They generate immune signals by presenting a vast repertoire of antigenic determinants and microbial metabolites that influence the development, maturation and maintenance of immunological function and homeostasis. At the same time, both the innate and adaptive immune systems are involved in modulating a stable microbial ecosystem between the commensal and pathogenic microorganisms. Hence, the gut microbial population and the host immune system work together to maintain immune homeostasis synergistically. In susceptible hosts, disruption of such a harmonious state can greatly affect human health and lead to various auto-inflammatory and autoimmune disorders. In this review, we discuss our current understanding of the interactions between the gut microbiota and immunity with an emphasis on: a) important players of gut innate and adaptive immunity; b) the contribution of gut microbial metabolites; and c) the effect of disruption of innate and adaptive immunity as well as alteration of gut microbiome on the molecular mechanisms driving autoimmunity in various autoimmune diseases.

PRICKLE1 gene methylation and abnormal transcription in Chinese patients with ankylosing spondylitis.

BACKGROUND: Ankylosing spondylitis (AS) is a common inflammatory arthritis without a reliable biomarker. The role of methylation and mRNA expression of PRICKLE1 promoter in the pathogenesis of ankylosing spondylitis remains unclear. METHODS: A two-stage case-control design was used to detect the characteristics of methyl group and transcriptome of PRICKLE1 gene in Ankylosing spondylitis. The methylation degree of PRICKLE1 gene promoter region was tested by phosphate-sequencing, and further analyzed whether there was significant difference in methylation level of PRICKLE1 gene. The expression levels of PRICKLE1 mRNA in 50 AS patients and 50 healthy controls were detected by real-time quantitative PCR (RT-qPCR). RESULTS: Compared with healthy control group, the intensity of methylation in 4 ponds of PRICKLE1 in patients with Ankylosing spondylitis was low, and the mRNA levels were overexpressed (P = 0.017). ROC results showed that the sensitivity of PRICKLE1 was 68.67% and specificity was 71.43%. CONCLUSION: There is a significant change in the concentration of serum PRICKLE1 mRNA​in patients with Ankylosing spondylitis, and the degree of gene methylation is significantly reduced, suggesting that PRICKLE1 gene maybe involved in the pathogenesis of Ankylosing spondylitis, which may be useful for predicting the occurrence of AS and finding new early screening indicators.

Efficacy and safety of tripterygium wilfordii Hook F plus TNF inhibitor for active rheumatoid arthritis: A multicentre, randomized, double-blind, triple-dummy controlled trial.

An investigator-initiated, multicentre, randomized, double-blind, triple-dummy, controlled trial was conducted at 14 tertiary rheumatology centers in China to evaluate the efficacy and safety of Tripterygium wilfordii Hook F (TwHF) with recombinant human TNF receptor IgGFc fusion protein (rhTNFR-Fc) in active Rheumatoid Arthritis (RA). Primary endpoint was the proportion of patients achieved a 50% improvement of American College of Rheumatology criteria (ACR50) in TwHF+rhTNFR-Fc vs. methotrexate (MTX) group at week 12. ACR50 was achieved in 57.1% (72/126), 41.3% (52/126), 23.0% (29/126), and 26.2% (33/126) patients receiving TwHF+rhTNFR-Fc, MTX + rhTNFR-Fc, TwHF and MTX monotherapy, respectively, at week 12 (TwHF+rhTNFR-Fc vs. other three groups, all p < 0.05). No statistical difference in serious adverse events or adverse events leading to discontinuation of study across all groups was documented. TwHF+rhTNFR-Fc was superior to MTX for active RA, and was more effective than MTX + rhTNFR-Fc on ACR50, with a similar safety profile. Trial registration:ClinicalTrials.govNCT03589833.

Frailty predicts knee pain trajectory over 9 years: results from the Osteoarthritis Initiative.

OBJECTIVE: Frailty is a multisystem syndrome and its relationship with symptomatic osteoarthritis has been reported. We aimed to identify trajectories of knee pain in a large prospective cohort and to describe the effect of frailty status at baseline on the pain trajectories over 9 years. METHODS: We included 4419 participants (mean age 61.3 years, 58% female) from the Osteoarthritis Initiative cohort. Participants were classified as "no frailty," "pre-frailty," or "frailty" at baseline, based on 5 characteristics (ie, unintentional weight loss, exhaustion, weak energy, slow gait speed, and low physical activity). Knee pain was evaluated annually using the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale (0-20) from baseline to 9 years. RESULTS: Of the participants included, 38.4%, 55.4%, and 6.3% were classified as "no frailty," "pre-frailty," and "frailty," respectively. Five pain trajectories were identified: "No pain" (n = 1010, 22.8%), "Mild pain" (n = 1656, 37.3%), "Moderate pain" (n = 1149, 26.0%), "Severe pain" (n = 477, 10.9%), and "Very Severe pain" (n = 127, 3.0%). Compared to participants with no frailty, those with pre-frailty and frailty were more likely to have more severe pain trajectories (pre-frailty: odds ratios [ORs] 1.5 to 2.1; frailty: ORs 1.5 to 5.0), after adjusting for potential confounders. Further analyses indicated that the associations between frailty and pain were mainly driven by exhaustion, slow gait speed, and weak energy. CONCLUSIONS: Approximately two-thirds of middle-aged and older adults were frail or pre-frail. The role of frailty in predicting pain trajectories suggests that frailty may be an important treatment target for knee pain.

No genetic causal association between systemic lupus erythematosus and COVID-19.

Objective: Emerging evidence suggests an increased prevalence of coronavirus disease 2019 (COVID-19) in patients with systemic lupus erythematosus (SLE), the prototype of autoimmune disease, compared to the general population. However, the conclusions were inconsistent, and the causal relationship between COVID-19 and SLE remains unknown. Methods: In this study, we aimed to evaluate the bidirectional causal relationship between COVID-19 and SLE using bidirectional Mendelian randomization (MR) analysis, including MR-Egger, weighted median, weighted mode, and the inverse variance weighting (IVW) method. Results: The results of IVW showed a negative effect of SLE on severe COVID-19 (OR = 0.962, p = 0.040) and COVID-19 infection (OR = 0.988, p = 0.025), which disappeared after Bonferroni correction. No causal effect of SLE on hospitalized COVID-19 was observed (OR = 0.983, p = 0.148). In the reverse analysis, no causal effects of severe COVID-19 infection (OR = 1.045, p = 0.664), hospitalized COVID-19 (OR = 0.872, p = 0.109), and COVID-19 infection (OR = 0.943, p = 0.811) on SLE were found. Conclusion: The findings of our bidirectional causal inference analysis did not support a genetically predicted causal relationship between SLE and COVID-19; thus, their association observed in previous observational studies may have been caused by confounding factors.

Could endothelial progenitor cells complement the diagnosis of inflammatory arthritis? A systematic review and meta-analysis.

The objective of this meta-analysis was to systematically review existing evidence and evaluate variations in levels of circulating endothelial progenitor cells (EPCs) among individuals with psoriatic arthritis (PsA), juvenile idiopathic arthritis (JIA), and rheumatoid arthritis (RA). Relevant studies were identified through database searches, and 20 records were enrolled. We used the fixed-effect model or random-effect model to estimate the pooled standardized mean difference (SMD) with 95% confidence intervals (CIs) in circulating EPC levels between inflammatory arthritis patients and controls. The results showed that circulating EPC levels differed among subtypes of inflammatory arthritis, with significantly lower levels in patients with RA (SMD = -0.848, 95% CI = -1.474 to -0.221, p = 0.008) and PsA (SMD = -0.791, 95% CI = -1.136 to -0.446, p < 0.001). However, no statistically significant difference was found in circulating EPC levels between patients with JIA and controls (SMD = -1.160, 95% CI = -2.578 to 0.259, p = 0.109). Subgroup analyses suggested that in patients with RA, circulating EPC levels were influenced by age, disease activity, and duration. Although many studies have investigated circulating EPC levels in patients with inflammatory arthritis, the results have been inconsistent. This meta-analysis offers a comprehensive overview of the existing evidence and emphasizes the association between levels of circulating EPCs and various types of arthritis. However, further research is needed to determine the specific mechanisms underlying the observed differences in EPC levels in different types of arthritis and to establish the clinical utility of this biomarker.

Triptoquinone A and B exercise a therapeutic effect in systemic lupus erythematosus by regulating NLRC3.

The autoimmune disorder systemic lupus erythematosus (SLE) is multifaceted, with limited therapeutic alternatives and detrimental side effects, particularly on bones and joints. This research endeavors to examine the curative potential and underlying mechanisms of in addressing SLE-associated bone and joint complications. Triptoquinone A and triptoquinone B, constituents of Tripterygium wilfordii polyglycoside tablets (TGTs), exhibit antioxidant and anti-inflammatory attributes; nonetheless, its function in SLE therapy remains elusive. This investigation delves into the role of oxidative stress in systemic lupus erythematosus (SLE) and probes the prospective remedial effects of triptoquinone A and triptoquinone B on inflammation and cartilage deterioration in SLE-affected joints. Employing bioinformatics analyses, differentially expressed genes (DEGs) and protein-protein interactions were discerned in SLE, rheumatoid arthritis (RA), and osteoarthritis (OA) datasets. Enrichment analyses unveiled shared genes implicated in immune system regulation and toll-like receptor signaling pathways, among others. Subsequent examination of triptoquinone A and triptoquinone B revealed their capacity to diminish NLRC3 expression in chondrocytes, resulting in decreased pro-inflammatory cytokine levels and cartilage degradation enzyme expression. Suppression of NLRC3 augmented the protective effects of triptoquinone A and B, implying that targeting NLRC3 may constitute a potential therapeutic strategy for inflammation and cartilage degeneration-associated conditions in SLE patients. Our discoveries indicate that triptoquinone A and triptoquinone B may impede SLE progression via the NLRC3 axis, offering potential benefits for SLE-affected bone and joint health.

Global burden and risk factors of musculoskeletal disorders among adolescents and young adults in 204 countries and territories, 1990-2019.

BACKGROUND: Current studies on musculoskeletal (MSK) disorders mainly focus on the elderly, while adolescents and young adults (AYAs) are often neglected despite their unique epidemiology, healthcare needs and societal implications. To bridge this gap, we evaluated the global burden and temporal trends of MSK disorders among AYAs from 1990 to 2019, as well as their common categories and main risk factors. METHODS: Data on the global burden and risk factors of MSK disorders were obtained from the Global Burden of Diseases study 2019. Age standardized rates for incidence, prevalence and disability-adjusted life-years (DALYs) were calculated using the world population age standard, and their temporal trends were evaluated by estimated annual percentage changes (EAPC). Locally estimated scatterplot smoothing (LOESS) regression was used to explore the association between two variables. RESULTS: Over the past 30 years, MSK disorders have become the third leading cause of global DALYs among AYAs, with 36.2%, 39.3%, and 21.2% of increases in incident cases, prevalent cases and DALYs, respectively. In 2019, age standardized incidence, prevalence and DALY rates for MSK disorders were positivity associated with socio-demographic index (SDI) among AYAs in 204 countries and territories. The global age-standardized prevalence and DALY rates of MSK disorders began to increases among AYAs since 2000. In the last decade, countries with high SDI not only presented the only increase in age-standardized incidence rate across all SDI quintiles (EAPC = 0.40, 0.15 to 0.65), but also displayed the most rapid increases in age-standardized prevalence and DALY rates (EAPC = 0.41, 0.24 to 0.57; 0.39, 0.19 to 0.58, respectively). Low back pain (LBP) and neck pain (NP) were the most common MSK disorders among AYAs, accounting for 47.2% and 15.4% of global DALYs of MSK disorders in this population, respectively. Rheumatoid arthritis (RA), osteoarthritis (OA), and gout exhibited increasing trends in global age-standardized incidence, prevalence, and DALY rates among AYAs over the past 30 years (all EAPC >0), whereas LBP and NP showed declining trends (all EAPC <0). Occupational ergonomic factors, smoking and high BMI accounted for 13.9%, 4.3%, and 2.7% of global DALYs for MSK disorders among AYAs, respectively. The proportion of DALYs attributable to occupational ergonomic factors was negatively associated with SDI, whereas the proportions attributable to smoking and high BMI increased with SDI. Over the last 30 years, both the proportions of DALYs attributable to occupational ergonomic factors and smoking have consistently decreased globally and across all SDI quintiles, while the proportion attributable to high BMI has increased. CONCLUSIONS: MSK disorders have emerged as the third leading cause of global DALYs among AYAs over the past three decades. Countries with high SDI should make more efforts to tackle the dual challenges posed by the high levels and rapid increases in age standardized incidence, prevalence, and DALY rates in the last decade.

Targeting immune checkpoints in anti-neutrophil cytoplasmic antibodies associated vasculitis: the potential therapeutic targets in the future.

Anti-neutrophil cytoplasmic autoantibodies (ANCA) associated vasculitis (AAV) is a necrotizing vasculitis mainly involving small blood vessels. It is demonstrated that T cells are important in the pathogenesis of AAV, including regulatory T cells (Treg) and helper T cells (Th), especially Th2, Th17, and follicular Th cells (Tfh). In addition, the exhaustion of T cells predicted the favorable prognosis of AAV. The immune checkpoints (ICs) consist of a group of co-stimulatory and co-inhibitory molecules expressed on the surface of T cells, which maintains a balance between the activation and exhaustion of T cells. CD28, inducible T-cell co-stimulator (ICOS), OX40, CD40L, glucocorticoid induced tumor necrosis factor receptor (GITR), and CD137 are the common co-stimulatory molecules, while the programmed cell death 1 (PD-1), cytotoxic T lymphocyte-associated molecule 4 (CTLA-4), T cell immunoglobulin (Ig) and mucin domain-containing protein 3 (TIM-3), B and T lymphocyte attenuator (BTLA), V-domain Ig suppressor of T cell activation (VISTA), T-cell Ig and ITIM domain (TIGIT), CD200, and lymphocyte activation gene 3 (LAG-3) belong to co-inhibitory molecules. If this balance was disrupted and the activation of T cells was increased, autoimmune diseases (AIDs) might be induced. Even in the treatment of malignant tumors, activation of T cells by immune checkpoint inhibitors (ICIs) may result in AIDs known as rheumatic immune-related adverse events (Rh-irAEs), suggesting the importance of ICs in AIDs. In this review, we summarized the features of AAV induced by immunotherapy using ICIs in patients with malignant tumors, and then reviewed the biological characteristics of different ICs. Our aim was to explore potential targets in ICs for future treatment of AAV.

Association of Sleep Disturbance With Catastrophizing and Knee Pain: Data From the Osteoarthritis Initiative.

OBJECTIVE: To investigate the relationship between sleep disturbance, catastrophizing, and knee pain in middle-aged and older individuals. METHODS: Data from the Osteoarthritis Initiative cohort from months 48 to 96 were used, where month 48 was treated as baseline. Knee pain (Western Ontario and McMaster Universities Osteoarthritis Index pain scale score ≥5 [range 0-20]), catastrophizing (extracted from Coping Strategies Questionnaire score ≥3 [range 0-6]), and sleep quality (extracted from Center for Epidemiologic Studies Depression Scale [range 1-4]) were assessed annually. We described the association of sleep disturbance with the presence and risk of knee pain and catastrophizing. The mediation effect of knee pain and catastrophizing on the sleep-catastrophizing and sleep-pain association was evaluated, respectively. RESULTS: Catastrophizing and knee pain were reported in 346 (10%) and 917 (24%) of the 3,813 participants (mean 64.9 years, 58% female) at baseline. Participants with worse sleep disturbance were more likely to have knee pain (prevalence ratio [PR] 1.4-2.0, P for trend <0.001) and catastrophizing (PR 1.4-3.1, P for trend <0.001). Sleep disturbance at baseline predicted the risk of knee pain (risk ratio [RR] 1.1, P for trend <0.001) and catastrophizing (RR 1.2-1.7, P for trend <0.001) during follow-up. No statistically significant interactions between sleep disturbance and knee pain or catastrophizing were observed. Knee pain and catastrophizing mediated the sleep-catastrophizing and sleep-pain association, respectively, at baseline, and knee pain negatively mediated the sleep-catastrophizing association longitudinally. CONCLUSION: Sleep disturbance was associated with the presence and risk of catastrophizing and knee pain. Sleep interventions may have a universal and independent effect in preventing incident knee pain.

Management of Rheumatoid Arthritis With a Digital Health Application: A Multicenter, Pragmatic Randomized Clinical Trial.

IMPORTANCE: Digital health applications have been shown to be effective in the management of chronic diseases with simple treatment targets. The potential clinical value of digital health applications in rheumatoid arthritis (RA) has not been well studied. OBJECTIVE: To investigate whether assessing patient-reported outcomes using digital health applications could result in disease control for patients with RA. DESIGN, SETTING, AND PARTICIPANTS: This is a multicenter, open-label randomized clinical trial in 22 tertiary hospitals across China. Eligible participants were adult patients with RA. Participants were enrolled from November 1, 2018, to May 28, 2019, with a 12-month follow-up. The statisticians and rheumatologists who assessed disease activity were blinded. Investigators and participants were not blind to group assignment. Analysis was conducted from October 2020 to May 2022. INTERVENTIONS: Participants were randomly assigned at a 1:1 ratio (block size of 4) to a smart system of disease management group (SSDM) or a conventional care control group. Upon the completion of the 6-month parallel comparison, patients in the conventional care control group were instructed to use the SSDM application for an extension of 6 months. MAIN OUTCOMES AND MEASURES: The primary outcome was the rate of patients with disease activity score in 28 joints using the C-reactive protein (DAS28-CRP) of 3.2 or less at month 6. RESULTS: Of 3374 participants screened, 2204 were randomized, and 2197 patients with RA (mean [SD] age, 50.5 [12.4] years; 1812 [82.5%] female) were enrolled. The study included 1099 participants in the SSDM group and 1098 participants in the control group. At month 6, the rate of patients with DAS28-CRP of 3.2 or less was 71.0% (780 of 1099 patients) in the SSDM group vs 64.5% (708 of 1098 patients) in the control group (difference between groups, 6.6%; 95% CI, 2.7% to 10.4%; P = .001). At month 12, the rate of patients with DAS28-CRP of 3.2 or less in the control group increased to a level (77.7%) that was comparable with that (78,2%) in the SSDM group (difference between groups, -0.2%; 95% CI, -3.9% to 3.4%; P = .90). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of RA, the use of a digital health application with patient-reported outcomes was associated with an increase in disease control rate. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03715595.