Rheumatoid arthritis and the risk of chronic kidney diseases: a Mendelian randomization study.

Background: The extra-articular lesions of rheumatoid arthritis (RA) are reported to involve multiple organs and systems throughout the body, including the heart, kidneys, liver, and lungs. This study assessed the potential causal relationship between RA and the risk of chronic kidney diseases (CKDs) using the Mendelian randomization (MR) analysis. Method: Independent genetic instruments related to RA and CKD or CKD subtypes at the genome-wide significant level were chosen from the publicly shared summary-level data of genome-wide association studies (GWAS). Then, we obtained some single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs), which are associated with RA in individuals of European origin, and had genome-wide statistical significance (p5 × 10-8). The inverse-variance weighted (IVW) method was the main analysis method in MR analysis. The other methods, such as weighted median, MR-Egger, simple mode, and weighted mode were used as supplementary sensitivity analyses. Furthermore, the levels of pleiotropy and heterogeneity were assessed using Cochran's Q test and leave-one-out analysis. Furthermore, the relevant datasets were obtained from the Open GWAS database. Results: Using the IVW method, the main method in MR analysis, the results showed that genetically determined RA was associated with higher risks of CKD [odds ratio (OR): 1.22, 95% confidence interval (CI) 1.13-1.31; p < 0.001], glomerulonephritis (OR: 1.23, 95% CI 1.15-1.31; p < 0.000), amyloidosis (OR = 1.43, 95% CI 1.10-1.88, p < 0.001), and renal failure (OR = 1.18, 95% CI 1.00-1.38, p < 0.001). Then, using multiple MR methods, it was confirmed that the associations persisted in sensitivity analyses, and no pleiotropy was detected. Conclusion: The findings revealed a causal relationship between RA and CKD, including glomerulonephritis, amyloidosis, and renal failure. Therefore, RA patients should pay more attention to monitoring their kidney function, thus providing the opportunity for earlier intervention and lower the risk of progression to CKDs.

Causal association between autoimmune liver disease and Sjögren's syndrome: A Mendelian randomization study.

BACKGROUND: Observational studies have found an association between autoimmune liver disease (AILD) and Sjögren's syndrome (SS). However, the causal relationship between the two remains unknown. Clinical guidelines indicate that the coexistence of AILD with other autoimmune diseases may impact prognosis and quality of life; hence, early recognition and management of extrahepatic autoimmune diseases is particularly crucial. Against this backdrop, this study aimed to utilize Mendelian randomization (MR) methods to investigate the potential causal relationship between AILD and SS. METHODS: We extracted summary statistics on AILD and SS from publicly available genome-wide association studies (GWAS) databases to identify appropriate instrumental variables (IVs). The inverse-variance weighted (IVW) method was utilized as the primary approach, with the weighted median (WM) method and MR-Egger method employed as supplementary methods to evaluate the potential causal relationship between the two conditions. Sensitivity analyses, including Cochran's Q test, MR-polynomial residuals and outliers (MR-PRESSO), MR-Egger intercept test, and the leave-one-out test, were performed to assess the stability of the results. RESULTS: The MR study results indicate a significant causal relationship between PBC and PSC with the risk of SS in the European population (IVW: odds ratio [OR] = 1.155, 95% confidence interval [CI]: 1.092-1.222, p < .001; IVW: OR = 1.162, 95% CI: 1.051-1.284, p = .003). A series of sensitivity analyses have confirmed the reliability of the results. CONCLUSIONS: Our study indicates that the presence of both PBC and PSC increases the susceptibility to SS. However, no reliable causal relationship was found between SS and the risk of PBC or PSC. These findings contribute to elucidating the potential pathogenic mechanisms of the disease and are of significant importance for the management of patients with PBC and PSC.

Causal relationships between Sjögren's syndrome and Parkinson's disease: A Mendelian randomization study.

BACKGROUND: Epidemiological and observational studies have indicated an association between Sjögren's syndrome (SS) and Parkinson's disease (PD). However, consistent conclusions have not been reached due to various limitations. In order to determine whether SS and PD are causally related, we conducted a Mendelian randomization study (MR) with two samples. METHODS: Data for SS derived from the FinnGen consortium's R9 release (2495 cases and 365 533 controls). Moreover, data for PD were acquired from the publicly available GWAS of European ancestry, which involved 33 674 cases and 449 056 controls. The inverse variance weighted, along with four other effective methodologies, were employed to comprehensively infer the causal relationships between SS and PD. To assess the estimation's robustness, a number of sensitivity studies were performed. To determine the probability of reverse causality, we performed a reverse MR analysis. RESULTS: There was no evidence of a significant causal effect of SS on PD risks based on the MR [odds ratio (OR) = 1.03; 95% confidence interval (CI) = 0.95-1.11; p = .45]. Similarly, no evidence supported the causal effects of PD on SS (OR = 0.92; 95% CI = 0.81-1.04; p = .20). These findings held up under rigorous sensitivity analysis. CONCLUSIONS: MR bidirectional analysis did not reveal any cause-and-effect relationship between SS and PD, or vice versa. Further study of the mechanisms that may underlie the probable causal association between SS and PD is needed.

Altered whole brain functional activity in patients with fibromyalgia.

OBJECTIVES: Fibromyalgia (FM) is a chronic pain disorder that takes a severe physical and psychological toll on patients and severely reduces their quality of life. In recent years, an increasing number of studies have used functional magnetic resonance imaging (fMRI) to investigate its pathogenesis. However, a recent summary analysis of functional connectivity in patients with FM is lacking. METHODS: We searched bibliographic databases, including PubMed, Web of Science (from inception until September 1st, 2022). Two separate researchers assessed the bias and quality of the studies. In order to further explain the core mechanism for FM, the abnormal brain function of FM was investigated by Activation Likelihood Estimation (ALE) analysis. RESULTS: Twenty-six FM publications (1,056 subjects) were eligible to be included in an ALE analysis. We found that the anterior cingulate (ACC) and insula (Ins) were abnormally active in patients with FM. In particular, the peak coordinates of (8,46,4) and (-46, -4,10) correspond to brain regions that were less active than healthy individuals. Furthermore, the Z-values were 4.46 and 4.97, while the p-values were 4.06 and 3.38. Surprisingly, we found that the degree of pain was negatively correlated with the activation of Ins (SDM-Z = -2.714). CONCLUSIONS: This study demonstrates abnormal brain activation which could lead to increased sensitivity of pain in patients with FM. The study sheds light on the central mechanisms of FM and provides the basis for further research.

Research trends and frontiers in lupus nephritis: a bibliometric analysis from 2012 to 2022.

OBJECTIVES: Lupus nephritis is a prevalent renal manifestation of systemic lupus erythematosus (SLE) and represents a significant cause of morbidity and mortality associated with the disease. This study endeavors to undertake a meticulous bibliometric analysis of LN publications to comprehend the research hotspots and future directions. METHODS: The literature on LN was acquired from the Web of Science Core Collection (WoSCC). Co-occurrence and cooperative relationship analysis of authors, institutions, countries, journals, references and keywords in the publication was performed through CiteSpace, VOSviewer and a bibliometric online analysis platform. The knowledge graphs were created, and clustering and emergence analyses were performed. RESULTS: According to the search strategy, a total of 2077 publications related to lupus nephritis (LN) have been identified, with China being the largest contributor globally. The Ohio State University emerged as the most prolific institution. Lupus is the most cited and published journal. Jan J Weening and Brad Rovin were the most prolific and cocited authors. The current research focus revolved around the "nirp3 inflammasome," "biomarker," and "voclosporin". "international society," "thrombotic microangiopathy (TMA)," and "pathway" were identified to be future research hotpots by keyword burst analysis. CONCLUSIONS: This bibliometric analysis summarizes for the first time the progress of LN research (2012-2022), and qualitatively and quantitatively evaluates the bibliometric information of LN research. There has been a steady increase in the scientific literature on LN over the past 11 years, with an average growth rate of 7.27%. In this field, researchers are primarily based in China and the United States. The pathogenic mechanisms, management strategies and prognostic outcomes of LN are acknowledged as prospective research hotspots. Bibliometrically, the research status and trends of LN publications may greatly assist and be a significant reference for future research in the area.

Postbiotics in rheumatoid arthritis: emerging mechanisms and intervention perspectives.

Rheumatoid arthritis (RA) is a prevalent chronic autoimmune disease that affects individuals of all age groups. Recently, the association between RA and the gut microbiome has led to the investigation of postbiotics as potential therapeutic strategies. Postbiotics refer to inactivated microbial cells, cellular components, or their metabolites that are specifically intended for the microbiota. Postbiotics not only profoundly influence the occurrence and development of RA, but they also mediate various inflammatory pathways, immune processes, and bone metabolism. Although they offer a variety of mechanisms and may even be superior to more conventional "biotics" such as probiotics and prebiotics, research on their efficacy and clinical significance in RA with disruptions to the intestinal microbiota remains limited. In this review, we provide an overview of the concept of postbiotics and summarize the current knowledge regarding postbiotics and their potential use in RA therapy. Postbiotics show potential as a viable adjunctive therapy option for RA.

Difficult-to-treat rheumatoid arthritis treated with Abatacept combined with Baricitinib: A case report.

BACKGROUND: Sporadic cases of rheumatoid arthritis (RA) due to unsatisfactory responses to Abatacept (ABT) have been reported; however, the rescue therapy has not been finalized. Here, we present a case with difficult-to-treat RA (D2T RA) that was resistant to either a single ABT or a Janus kinase (JAK) inhibitor (Tofacitinib), but improved with a combination of ABT and JAK inhibitor (Baricitinib, BAT). CASE SUMMARY: A 46-year-old Chinese woman who had RA for ten years that was resistant to Tocilizumab, Etanercept, Adalimumab, and ABT. According to the European League Against Rheumatism definition, the patient was diagnosed with D2T RA. It was then improved with a combination of ABT and a JAK inhibitor BAT. CONCLUSION: ABT combined with BAT may be an acceptable strategy for treating D2T RA.

Maternal and fetal outcomes in pregnant women with rheumatoid arthritis: a systematic review and meta-analysis.

OBJECTIVE: Rheumatoid arthritis (RA) is a common chronic systemic autoimmune disease affecting women of childbearing age. We aimed to conduct a meta-analysis of published observational studies to systematically evaluate the association between RA and adverse pregnancy outcomes. METHODS: Medline (PubMed), EMBASE, and Web of Science were searched for keywords from the date of inception to December 28, 2021, to identify relevant studies reporting adverse maternal and/or fetal outcomes in RA pregnancies. Data from individual studies were pooled using random-effects models and presented as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Eighteen studies with a total number of over 50 million participants were eligible for inclusion. This current analysis showed that in pregnant women with RA, there was a significantly increased risk of adverse maternal outcomes, including caesarean section (OR, 1.39; 95% CI 1.24-1.55), pre-eclampsia (OR, 1.48; 95% CI 1.19-1.83), gestational hypertension (OR, 1.34; 95% CI 1.07-1.68) and spontaneous abortion (OR, 1.16; 95% CI 1.04-1.29). Similarly, maternal RA during pregnancy was also associated with a significantly increased risk of adverse fetal outcomes, including preterm birth (OR, 1.58; 95% CI 1.44-1.74), small for gestational age (OR, 1.49; 95% CI 1.22-1.82), low birth weight (OR, 1.45; 95% CI 1.30-1.63), congenital anomalies (OR, 1.36; 95% CI 1.01-1.83) and stillborn (OR, 1.38; 95% CI 1.09-1.74). CONCLUSION: Maternal RA is significantly associated with an increased risk of adverse maternal and fetal outcomes. Close monitoring of the clinical status of RA patients before and during pregnancy is essential in clinical practice. Key Points • Pregnant women with rheumatoid arthritis (RA) are at significantly increased risk for adverse maternal and fetal outcomes. • The increased risk of adverse pregnancy outcomes in women with RA may be closely related to medication use and disease activity. • Close monitoring of the clinical status of RA patients before and during pregnancy is essential in clinical practice.

A bibliometric analysis of idiopathic inflammatory myopathies from 1982 to 2021.

OBJECTIVE: There has been an increasing number of literature related to idiopathic inflammatory myopathies (IIM) in the past few decades. However, there is a lack of intuitive and systematic analysis of research on IIM. Therefore, this study aimed to perform a bibliometric analysis to identify the current trends and hotspots of research on IIM. METHODS: Articles and reviews on IIM published during 1982-2021 were acquired from the Web of Science Core Collection (WoSCC) database. VOSviewer application was applied to conduct a network analysis of the keywords, institutions, and countries. The top 100 most-cited publications regarding IIM were analyzed. RESULTS: In total, 665 publications were included. Globally, the USA produced the most articles on IIM (144). Karolinska Institutet was the institution with the most outputs (47). Rheumatology ranked on top of journals, with 47 IIM-related documents collecting a total of 1420 citations. In the area of IIM documents, biomarkers were the most common research theme. According to the co-occurrence analysis of keywords, "cardiac involvement," "criteria," and "refractory adult" were identified as significant future research centers. CONCLUSION: The scientific literature on IIM has advanced rapidly in the past 4 decades. The classification criteria, treatment, and extramuscular manifestations of IIM have been identified as promising research frontiers in the field. The global status and trends of the IIM literature from a bibliometric aspect can offer a helpful guidance and new insight for researchers and medical workers in the domain. Key Points • This study reveals the topic trends and knowledge structure of idiopathic inflammatory myopathies literature over the last 40 years. • This study identifies potential future research hotspots, including "cardiac involvement," "criteria," and "refractory adult."

Association between type 1 diabetes mellitus and ankylosing spondylitis: a two-sample Mendelian randomization study.

Objective: The development of ankylosing spondylitis (AS) is closely related to autoimmune system dysfunction. Type 1 diabetes mellitus (T1DM) is an autoimmune disease that is a risk factor for many diseases. This study aimed to investigate the causal relationship between T1DM mellitus and AS genetically. Methods: A genome-wide association study (GWAS) of causal relationships between exposure (T1DM) and outcome (AS) was performed using summary data from the GWAS database. We conducted a two-sample Mendelian randomization (MR) study of these two diseases. Inverse variance weighting (IVW) was used as the primary analysis method, with MR Egger, weighted median, and weighted mode used as supplementary methods. Sensitivity analyses were performed using Cochran's Q test, MR-Egger intercept, MR-Pleiotropy RESidual Sum and outlier methods, leave-one-out analysis, and funnel plots. Results: A total of 11 single nucleotide polymorphisms (SNPs)were identified for instrumental variables(IVs) for MR analysis.IVW found that T1DM was causally associated with AS ((IVW: OR = 1.0006 (95% CI 1.0001, 1.0011), p = 0.0057; MR-Egger: OR = 1.0003 (95% CI 0.9995, 1.0012), p = 0.4147; weighted median: OR = 1.0006 (95% CI 1.0003, 1.0008), p = 0.0001; weighted mode: OR = 1.0007 (95% CI 1.0005, 1.0009), p = 0.0001). No horizontal pleiotropy was found for the MR-Egger intercept, and leave -one-out analysis found that the results remained stable after the removal of individual SNPs. Conclusion: The results of the two-sample MR analysis supported a causal relationship between T1DM and AS risk.

Causal association between systemic lupus erythematosus and the risk of dementia: A Mendelian randomization study.

Introduction: It is well-documented that systemic lupus erythematosus (SLE) is associated with dementia. However, the genetic causality of this association remains unclear. Mendelian randomization (MR) was used to investigate the potential causal relationship between SLE and dementia risk in the current study. Methods: We selected 45 single nucleotide polymorphisms (SNPs) associated with SLE from publicly available genome-wide association studies (GWAS). Summary level statistics were obtained from the dementia GWAS database. MR estimates were performed using the inverse variance weighted (IVW) method, MR-Egger method and weighted median (WM) method. Cochran's Q test, the intercept of MR-Egger, MR-Pleiotropy Residual Sum and Outlier method, leave-one-out analysis and funnel plot were applied for sensitivity analyses. Results: No significant causal association was found between SLE and any type of dementia, including Alzheimer's disease, vascular dementia, frontotemporal dementia, and dementia with Lewy bodies. These findings were robust across several sensitivity analyses. Conclusion: Overall, our findings do not support a causal association between SLE and dementia risk.

Causal association between adiponectin and the risk of Alzheimer's disease: A Mendelian randomization study.

Background: Numerous observational studies have revealed that circulating adiponectin (ADPN) is associated with Alzheimer's disease (AD) risk. However, the causality remains unknown. We aimed to assess the causality of circulating ADPN on AD risk using Mendelian randomization (MR). Methods: Fourteen single nucleotide polymorphisms (SNPs) significantly associated with ADPN were selected from publicly available genetic abstract data. We applied these SNPs to two recent large-scale genome-wide association studies (GWAS) of AD, one from the FinnGen consortium and the other from a large meta-analysis. The inverse variance weighted method, MR-Egger method, the weighted median method, the Cochran Q statistic, the MR-Pleiotropy Residual Sum and Outlier methods, and the leave-one-out analysis were applied for MR analyses. Results: In MR analysis, no significant genetic association was found between plasma ADPN levels and AD risk by analyzing the FinnGen consortium GWAS database in the inverse variance weighted method [odds ratio (OR): 0.874, 95% confidence interval (CI): 0.701-1.089, p = 0.230], MR-Egger (OR: 0.944, 95% CI: 0.692-1.288, p = 0.721), and weighted median method (OR: 0.900, 95% CI: 0.678-1.194, p = 0.449). Additionally, the same analysis was conducted for the meta-analysis database, and we found no significant association (OR: 1.000, 95% CI: 0.999-1.001, p = 0.683). Conclusion: Our findings reveal no significant causal association between circulating ADPN and AD risk.

Research trends and frontiers on antiphospholipid syndrome: A 10-year bibliometric analysis (2012-2021).

Objectives: A growing body of studies related to antiphospholipid syndrome (APS) have been published in recent years. Nevertheless, there is a lack of visualized and systematic analysis in the literature on APS. Hence, this study sought to conduct a bibliometric analysis to identify research status and discover frontiers in the field. Methods: Articles and reviews concerning APS were acquired from the Web of Science Core Collection (WoSCC) database. CiteSpace, VOSviewer and a bibliometric online analysis platform were employed to conduct a visualization and knowledge-map analysis. Results: A total of 1,390 publications regarding APS were identified. Globally, Italy contributed the most publications. The University of Padua was the most productive institution. Lupus ranked first in both the most published and most co-cited journals. Savino Sciascia and Spiros Miyakis were the most prolific and most co-cited authors, respectively. "Vitamin K antagonists (VKA)" and "immunoglobulin A (IgA)" were current research foci. Burst analysis of keywords suggested that "neutrophil extracellular trap (NET)," "direct oral anticoagulant (DOAC)," "open label," "outcome," "hydroxychloroquine (HCQ)," and "arterial thrombosis (AT)" were significant future research frontiers. Conclusion: The scientific literature on APS has increased steadily in the past 10 years. The clinical studies on the treatment and mechanism research of APS are recognized as promising research hotspots in the domain of APS. The research status and trends of APS publications from the bibliometric perspective can provide a practical guide and important reference for subsequent studies by researchers and physicians in the domain.

Bibliometric Analysis of the Scientific Literature on Rheumatoid Arthritis-Associated Interstitial Lung Disease.

BACKGROUND: In recent years, the number of studies on rheumatoid arthritis-related interstitial lung disease (RA-ILD) has been increasing, which has led to many publications on this topic. Our purpose is to identify research trends in RA-ILD and analyze the most-cited RA-ILD-related high-quality scientific publications. METHODS: All publications on RA-ILD in the Core Collection database of Web of Science were searched. The publication year, country, institution, total citations, and journal were extracted and analyzed. We used VOSviewer software or an online bibliometric analysis platform for cooccurrence analysis of the keywords, institutions, and countries involved. The 100 most frequently cited RA-ILD publications were analyzed. RESULTS: In total, 596 publications related to RA-ILD were obtained. Over time, the frequency of RA-ILD publications has increased. Globally, the United States provides the most publications on RA-ILD (n = 195). The institution with the highest publication output was the Mayo Clinic (n = 43). The journal "Annals of the Rheumatic Diseases" published most with 93 articles and received 338 citations. A clinical description was the most common research topic in RA-ILD-related publications. CONCLUSIONS: In recent years, there has been an increasing number of studies on RA-ILD, and related publications have increased rapidly. This study is the first bibliometric study of RA-ILD-related publications. It can be used as a guide for clinicians and can help researchers choose research directions of interest in this field.

The effects of iguratimod combined with methotrexate and hydroxychloroquine on bone mineral density in patients with rheumatoid arthritis.

In this study, we aimed to explore the effects of iguratimod (IGU) combined with methotrexate (MTX) and hydroxychloroquine (HCQ) on bone mineral density (BMD) in patients with rheumatoid arthritis (RA). 76 patients who received IGU combined with MTX and HCQ were included in this retrospective study. After 48 weeks treatment of IGU combined with MTX and HCQ, the BMD at the L1-L4 (p <0.01), left femoral neck (p <0.01) and left total hip (p <0.01) were significantly increased. Especially, the BMD at left femoral neck was significantly increased from baseline to week 24 (p <0.05). With regard to inflammatory reaction, there were statistically significant reductions in the RF (p <0.05), CRP (p <0.05), ESR (p <0.01), anti-CCP (p <0.01) from baseline to week 48. The most common adverse events were gastrointestinal reaction and transaminase elevation. The combination of IGU, MTX and HCQ could significantly improve the BMD and restrain inflammatory reaction. No additional adverse events were noticed in our research. This study provides valuable information for treatment of osteopenia in patients with RA.

Iridin Prevented Against Lipopolysaccharide-Induced Inflammatory Responses of Macrophages via Inactivation of PKM2-Mediated Glycolytic Pathways.

PURPOSE: Abnormal glycolysis of immune cells contributed to the development of inflammatory response. Inhibition of this Warburg phenotype could be a promising strategy for preventing various inflammatory diseases. Iridin (IRD) is a natural isoflavone, and exerts anticancer, antioxidant, and anti-inflammatory effects. However, the underlying mechanism of IRD on acute inflammation remains unknown. In this study, the protective effects of IRD against lipopolysaccharide (LPS)-induced inflammation were investigated in murine macrophage RAW264.7 cells and in mice. METHODS: The inhibition of IRD on NO production in culture medium was detected by Griess assay while the levels of TNF-α, IL-1ß, and MCP-1 were detected by ELISA assay. The effects of IRD on OCR and ECAR levels in LPS-treated macrophages were monitored by using Seahorse Analyzer. The apoptosis rate as well as the release of ROS and NO of RAW264.7 cells were analyzed by flow cytometric assay. The protective effects of IRD were investigated on LPS-induced inflammation in mice. The expressions of PKM2 and its downstream (p-JAK1, p-STAT1, p-STAT3, p-p65, iNOS, and COX2) in cells and in lung tissues were detected by Western blotting analysis. RESULTS: IRD treatment at the concentrations of 12.5-50 µM significantly inhibited the productions of TNF-α, IL-1ß, MCP-1, and ROS, and suppressed the levels of glucose uptake and lactic acid in LPS-treated RAW264.7 cells. Oral administration with IRD (20-80 mg/kg) inhibited LPS-induced acute lung injury as well as inflammatory cytokine production in mice. Moreover, IRD targeted pyruvate kinase isozyme type M2 (PKM2) and suppressed its downstream p-JAK1, p-STAT1, p-STAT3, p-p65, iNOS, and COX2, which could be abolished by PKM2 agonist DASA-58 and antioxidant N-acetyl-L-cysteine, but partly be reversed by NF-κB activator CUT129 and JAK1 activator RO8191. CONCLUSION: IRD alleviated LPS-induced inflammation through suppressing PKM2-mediated pathways, and could be a potential candidate for the prevention of inflammatory diseases.