Association Between Hashimoto's Thyroiditis and Rheumatoid Arthritis: A Bidirectional Mendelian Randomization Study.

Background: We aim to investigate the possible causal association between Hashimoto's thyroiditis (HT) and rheumatoid arthritis (RA) using Mendelian randomization (MR) methods. Methods: A bidirectional MR analysis was conducted to evaluate the causal association between HT and RA. We obtained summary statistics data from two extensive genome-wide association studies (GWAS) comprising 15,654 cases of HT and 14,361 cases of RA. The primary effect estimate utilized in this study was the inverse-variance weighted (IVW) method. To ensure the reliability and stability of the results, we employed several additional methods for testing, including MR-Egger, weighted median, simple mode, weighted mode, and MR-PRESSO. Results: Our study revealed compelling evidence of bidirectional causality between HT and RA. When HT was considered as an exposure factor and RA was considered as an outcome factor, this study revealed a positive correlation between HT and RA (IVW: odds ratio [OR] = 2.4546, 95% confidence interval [CI], 1.1473-5.2512; p = 0.0207). Conversely, when we examined RA as the exposure factor and HT as the outcome factor, we still found a positive correlation between them (IVW: OR = 1.2113, 95% CI, 1.1248-1.3044; p = 3.9478 × 10-7). Conclusions: According to our research findings, there exists a bidirectional positive causal relationship between HT and RA among European populations. This implies that individuals with HT have an elevated risk of developing RA, and conversely, individuals with RA have an increased risk of developing HT.

Metformin Treatment Reduces the Incidence of Rheumatoid Arthritis: A Two-Sample Mendelian Randomized Study.

Several studies have shown that rheumatologic patients can benefit from metformin, but it remains unclear whether metformin treatment is causally associated with the risk of rheumatoid arthritis (RA). A two-sample Mendelian randomization (MR) study was conducted to investigate the causal relationship between metformin treatment and the incidence of rheumatoid arthritis. The genome-wide significant (p < 5 × 10-8) single-nucleotide polymorphisms (SNPs) associated with metformin use were selected as instrumental variables (IVs). Summary statistics on RA were extracted from a large genome-wide association study (GWAS) meta-analysis. The inverse variance-weighted (IVW) method was used as the determinant of the causal effects of metformin treatment on RA. Cochran's Q was used to detect heterogeneity. Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test and MR-Egger regression were used to detect horizontal pleiotropy. A total of 34 SNPs significantly associated with metformin treatment were obtained. Thirty-two SNPs were selected as IVs after removing two SNPs for being palindromic with intermediate allele frequencies (rs11658063 and rs4930011). The IVW results showed a negative causal association between metformin treatment and RA (OR = 0.0232, 95% CI 1.6046 × 10-3 - 0.3368; p = 0.006). Meanwhile, no heterogeneity or pleiotropy was detected, indicating that the results were reliable. This study indicated a negative causality between metformin treatment and RA, indicating that the treatment of metformin can prevent the pathogenesis of RA.

The Burden of Rheumatoid Arthritis: Findings from the 2019 Global Burden of Diseases Study and Forecasts for 2030 by Bayesian Age-Period-Cohort Analysis.

BACKGROUND: Rheumatoid arthritis (RA) is a key health issue worldwide. Due to early identification and effective treatment strategies, the disease pattern of RA has also changed. However, the most comprehensive and up-to-date information about the burden of RA and its trends in subsequent years is lacking. OBJECTIVE: this study aimed to report the global burden of RA by sex, age, region, and forecast for 2030. METHOD: Publicly available data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 were used in this study. The trends in the prevalence, incidence, and disability-adjusted life years (DALYs) of RA from 1990 to 2019 were reported. The global burden of RA in 2019 was reported by a sex, age, and sociodemographic index (SDI). Finally, the trends in the following years were predicted by Bayesian age-period-cohort (BAPC) models. RESULTS: Globally, the age-standardized prevalence rate increased from 207.46 (95% UI:189.99 to 226.95) in 1990 to 224.25 (95% UI: 204.94 to 245.99) in 2019, with an estimated annual percent change (EAPC) of 0.37% (95% CI: 0.32 to 0.42). Regarding the incidence, the age-standardized incidence rate (ASR) increased from 12.21 (95% UI: 11.13 to 13.38) to 13 (95% UI: 11.83 to 14.27) per 100,000 people from 1990 to 2019, with an EAPC of 0.3% (95% CI: 11.83 to 14.27). The age-standardized DALY rate also increased from 39.12 (95% UI: 30.13 to 48.56) per 100,000 people in 1990 to 39.57 (95% UI: 30.51 to 49.53) in 2019, with an EAPC of 0.12% (95% CI: 0.08% to 0.17%). There was no significant association between the SDI and ASR when the SDI was lower than 0.7, while there was a positive association between the SDI and ASR when the SDI was higher than 0.7 The BAPC analysis showed that the ASR was estimated to be up to 18.23 in females and approximately 8.34 per 100,000 people in males by 2030. CONCLUSION: RA is still a key public health issue worldwide. The global burden of RA has increased over the past decades and will continue to increase in the coming years, and much more attention should be given to early diagnosis and treatment to reduce the burden of RA.

Synovial fluid neutrophil extracellular traps could improve the diagnosis of periprosthetic joint infection.

AIMS: This study aimed to explore the diagnostic value of synovial fluid neutrophil extracellular traps (SF-NETs) in periprosthetic joint infection (PJI) diagnosis, and compare it with that of microbial culture, serum ESR and CRP, synovial white blood cell (WBC) count, and polymorphonuclear neutrophil percentage (PMN%). METHODS: In a single health centre, patients with suspected PJI were enrolled from January 2013 to December 2021. The inclusion criteria were: 1) patients who were suspected to have PJI; 2) patients with complete medical records; and 3) patients from whom sufficient synovial fluid was obtained for microbial culture and NET test. Patients who received revision surgeries due to aseptic failure (AF) were selected as controls. Synovial fluid was collected for microbial culture and SF-WBC, SF-PNM%, and SF-NET detection. The receiver operating characteristic curve (ROC) of synovial NET, WBC, PMN%, and area under the curve (AUC) were obtained; the diagnostic efficacies of these diagnostic indexes were calculated and compared. RESULTS: The levels of SF-NETs in the PJI group were significantly higher than those of the AF group. The AUC of SF-NET was 0.971 (95% confidence interval (CI) 0.903 to 0.996), the sensitivity was 93.48% (95% CI 82.10% to 98.63%), the specificity was 96.43% (95% CI 81.65% to 99.91%), the accuracy was 94.60% (95% CI 86.73% to 98.50%), the positive predictive value was 97.73%, and the negative predictive value was 90%. Further analysis showed that SF-NET could improve the diagnosis of culture-negative PJI, patients with PJI who received antibiotic treatment preoperatively, and fungal PJI. CONCLUSION: SF-NET is a novel and ideal synovial fluid biomarker for PJI diagnosis, which could improve PJI diagnosis greatly.Cite this article: Bone Joint Res 2023;12(2):113-120.

Exosomes derived from M2 macrophages induce angiogenesis to promote wound healing.

There is an urgent clinical need for an appropriate method to shorten skin healing time. Among most factors related to wound healing, M2 macrophages will be recruited to the wound area and play a pivotal role in a time-limiting factor, angiogenesis. The exploration of exosomes derived from M2 in angiogenesis promotion is an attractive research field. In this project, we found that exosomes from M2 (M2-EXO) promoted the angiogenic ability of HUVECs in vitro. With a series of characteristic experiments, we demonstrated that M2-EXO inhibited PTEN expression in HUVECs by transferring miR-21, and further activated AKT/mTOR pathway. Then, using a full-thickness cutaneous wound mice model, we demonstrated that M2-EXO could be used as a promotor of angiogenesis and regeneration in vivo. Furthermore, M2-EXO-treated skin wounds exhibited regeneration of functional microstructures. These results demonstrate that M2-EXO can be used as a promising nanomedicine strategy for therapeutic exploration of skin healing with the potential to be translated into clinical practice.

Causal relationships between rheumatism and dyslipidemia: A two-sample Mendelian randomization study.

Background: Dyslipidemia is often observed in rheumatic diseases, such as ankylosing spondylitis (AS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE), yet it remains to be detected whether rheumatic diseases have a causal effect on dyslipidemia. Methods: Significant (P < 5 × 10-8) and independent (r2 < 0.1) single-nucleotide polymorphisms in genome-wide association studies were selected as instrumental variables to conduct Mendelian randomization (MR) analysis. Inverse variance weighted, weighted median, and MR-Egger regression were adopted for the causal inference. Subsequently, sensitivity analysis was conducted to assess the stability and reliability of MR. Results: The MR results revealed positive causal relationships of AS with total cholesterol (TC) (ß = 0.089, 95% CI = 0.050 to 0.128, P = 6.07 × 10-6), low-density lipoprotein (LDL) (ß = 0.087, 95% CI = 0.047 to 0.127, P = 1.91 × 10-5), and high-density lipoprotein (HDL) (ß = 0.043, 95% CI = 0.001 to 0.074, P = 0.009). There was no causal effect of RA on TC (ß = 0.008, 95% CI = 4.86 × 10-4 to 0.017, P = 0.064), LDL (ß = 6.4 × 10-4, 95% CI = -0.008 to 0.007, P = 0.871), or HDL (ß = 0.005, 95% CI = -0.003 to 0.013, P = 0.200). Additionally, SLE had negative causal links for TC (ß = -0.025, 95% CI = -0.036 to -0.015, P = 4.42 × 10-6), LDL (ß = -0.015, 95% CI = -0.025 to -0.005, P = 0.003), and HDL (ß = -0.013, 95% CI = -0.021 to -0.004, P = 0.004). The results were stable and reliable. Conclusion: This study suggested positive causal effects of AS on TC, LDL, and HDL and negative causal effects of SLE on these cholesterol levels, which could provide much help for the pathogenesis and treatment of rheumatic disease patients with dyslipidemia.

The relationship between central obesity and bone mineral density: a Mendelian randomization study.

BACKGROUND: The relationship between obesity and osteoporosis is an important public health issue. The goal of this study was to investigate whether and to what extent central obesity traits affect bone mineral density (BMD). METHODS: We conducted a two-sample Mendelian randomization analysis. Genomewide significant single nucleotide polymorphisms associated with waist circumference, hip circumference, waist-to-hip ratio, waist circumference adjusted by body mass index (WCadjBMI), hip circumference adjusted by BMI (HCadjBMI) and waist-to-hip ratio adjusted by BMI (WHRadjBMI) were obtained from a large-scale database containing 224,459 samples. The BMD summary dataset was obtained from a UK Biobank database including 265,627 participants. RESULTS: The results provided strong evidence that the HCadjBMI trait was causally and negatively associated with BMD (ß: - 0.135, 95% CI - 0.216 to - 0.054; P = 0.001), while the WHR trait was causally and positively associated with BMD (ß: 0.194, 95% CI 0.062 to 0.325, P = 0.004). No significant effects were observed for other traits on BMD. CONCLUSIONS: This study indicates variations in the abilities of different central obesity traits to influence BMD. These results should be considered in further studies and public health measures on obesity and osteoporosis prevention strategies.

The Causal Relationship Between Rheumatoid Arthritis and Mechanical Complications of Prosthesis After Arthroplasty: A Two-Sample Mendelian Randomization Study.

The causal effects of rheumatoid arthritis (RA) on complications of arthroplasty are yet to be established. This study was the first to explore the causal effect of RA on mechanical complications of prosthesis through two-sample Mendelian randomization (MR). In the MR analysis, RA was selected as the exposure in this study while single-nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS) were selected as the instrumental variables (IVs). Summary statistics data on mechanical complications of prosthesis was extracted from publicly available GWAS data, including 463,010 European descent individuals. MR analysis was performed using the standard inverse variance weighted method (IVW). Furthermore, other methods (MR Egger, weighted median, simple mode, and weighted mode) were also done to verify the results. Finally, the sensitivity analysis was executed. Results of the standard IVW showed that RA possibly increases the risk of mechanical complications of prosthesis [OR = 1.000255; 95% CI = (1.0001035, 1.000406); p = 9.69 × 10 -4 ]. This outcome was also verified by other methods including weighted median [OR = 1.000285; 95% CI = (1.0001032, 1.000466); p = 1.41 × 10-3], simple mode [OR = 1.000446; 95% CI = (1.0001116, 1.000781); p = 1.04 × 10-2], and weighted mode [OR = 1.000285; 95% CI = (1.0001032, 1.000466); p = 2.29 × 10-3]. No heterogeneity and directional pleiotropy was observed upon sensitivity analysis, indicating the stability and reliability of the result. In summary, the present study showed that RA potentially increases the risks of complications of prosthesis, which might provide guidance in arthroplasty on RA patients.

Causal Relationships of General and Abdominal Adiposity on Osteoarthritis: A Two-Sample Mendelian Randomization Study.

Background: Adiposity is closely related to osteoarthritis, but the causal effects of different types of adiposity on osteoarthritis are indistinct. This study conducted a Mendelian Randomization (MR) analysis for the causal effects of general adiposity and abdominal adiposity on knee osteoarthritis (KOA) and hip osteoarthritis (HOA). Methods: The general adiposity was assessed by body mass index (BMI), while the abdominal adiposity was evaluated with waist circumference (WC), hip circumference (HC), and waist-to-hip ratio (WHR). The data used in this two-sample MR analysis originated from genome-wide association studies (GWAS). Significant (p < 5 × 10−8) and independent (r2 < 0.01) single-nucleotide polymorphisms were selected as instrumental variables for the MR analysis. Subsequently, this study used the inverse variance weighted, weighted median, and other methods for the causal inference, and the results were presented as odds ratios (OR). Moreover, sensitivity analyses were conducted to assess the stability and reliability of the results. Results: The MR results revealed positive causal effects of BMI on KOA (OR: 1.694; 95% CI: from 1.492 to 1.923; p = 3.96 × 10−16) and HOA (OR: 1.412; 95% CI: from 1.196 to 1.666; p = 4.58 × 10−5). Additionally, WC and HC both positively and causally related to KOA (WC: OR: 1.827; 95% CI: from 1.564 to 2.134; p = 2.68 × 10−14; HC: OR: 1.610; 95% CI: from 1.357 to 1.912; p = 5.03 × 10−8) and HOA (WC: OR: 1.491; 95% CI: from 1.254 to 1.772; p = 5.85 × 10−6; HC: OR: 1.439; 95% CI: from 1.205 to 1.719; p = 5.82 × 10−5). However, no causal relationship existed between WHR and obesity. These results were robust according to the sensitivity analyses. Conclusions: This study indicated that both general and abdominal obesity had positive causal effects on knee osteoarthritis and hip osteoarthritis.

Exosomes from miRNA-378-modified adipose-derived stem cells prevent glucocorticoid-induced osteonecrosis of the femoral head by enhancing angiogenesis and osteogenesis via targeting miR-378 negatively regulated suppressor of fused (Sufu).

BACKGROUND: Local ischemia and defective osteogenesis are implicated in the progression of glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH). Recent studies have revealed that exosomes released from adipose-derived stem cells (ASCs) play important roles in ONFH therapy. The present study aimed to investigate whether exosomes derived from miR-378-overexpressing ASCs (miR-378-ASCs-Exos) could promote angiogenesis and osteogenesis in GC-induced ONFH. METHODS: In vitro, we investigated the osteogenic potential of miR-378-ASCs-Exos on bone marrow stromal cells (BMSCs) by alkaline phosphatase staining and western blotting. The angiogenic effects of miR-378-ASCs-Exos on human umbilical vein endothelial cells (HUVECs) were examined by evaluating their proliferation, migration, and tube-forming analyses. We identified the underlying mechanisms of miR-378 in osteogenic and angiogenic regulation. In addition, an ONFH rat model was established to explore the effects of miR-378-ASCs-Exos through histological and immunohistochemical staining and micro-CT in vivo. RESULTS: Administration of miR-378-ASCs-Exos improved the osteogenic and angiogenic potentials of BMSCs and HUVECs. miR-378 negatively regulated the suppressor of fused (Sufu) and activated Sonic Hedgehog (Shh) signaling pathway, and recombinant Sufu protein reduced the effects triggered by miR-378-ASCs-Exos. In vivo experiments indicated that miR-378-ASCs-Exos markedly accelerated bone regeneration and angiogenesis, which inhibited the progression of ONFH. CONCLUSION: Our study indicated that miR-378-ASCs-Exos enhances osteogenesis and angiogenesis by targeting Sufu to upregulate the Shh signaling pathway, thereby attenuating GC-induced ONFH development.

Causal Relationships Between Osteoarthritis and Senile Central Nerve System Dysfunction: A Bidirectional Two-Sample Mendelian Randomization Study.

Background: The relationship between osteoarthritis (OA) and senile central nervous system dysfunctions (CNSDs), including Parkinson's disease (PD), Alzheimer's disease (AD), and ischemic stroke (IS) has gradually attracted attention. At present, the causal relationship between OA and CNSD remains unclear. The aim of this study was to assess the causal effects of CNSD and OA using Mendelian randomization (MR). Methods: Genome-wide association study summary data for CNSD and OA were obtained. Single-nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs), and significant (P < 5.0 × 10-8) and independent (r 2 < 0.1) SNPs were extracted for bidirectional MR analysis. Inverse variance weighted (IVW) was used to assess these causal relationships. The results are reported as odds ratios (ORs). Subsequently, heterogeneity was tested using the Cochran's Q test, pleiotropy was tested using the MR-Egger intercept, and sensitivity analysis was performed using the leave-one-out sensitivity test. Results: The MR results of the causal relationship between PD and OA showed that there was a positive causal effect of OA on PD, which was estimated by IVW (OR = 1.194, 95%CI = 1.036, 1.378; P = 0.0144). Moreover, the MR analysis by IVW also showed that IS had a positive effect on OA (OR = 1.033, 95%CI = 1.002, 1.066; P = 0.0355). These results are reliable and stable, as confirmed by sensitivity tests. Conclusion: This study showed a positive causal effect of OA on PD, but there was a null effect of OA on AD and OA on IS.