The Causal Relationship between PCSK9 Inhibitors and Osteoporosis Based on Drug-Targeted Mendelian Combined Mediation Analysis.

PCSK9 inhibitors have been shown to lower serum low density lipoprotein cholesterol (LDL-C) levels and are considered integral in the treatment of cardiovascular diseases. However, the potential association between PCSK9 inhibitors and osteoporosis is unclear now. In this study, drug-targeted mendelian randomization (MR) was utilized in conjunction with mediation analysis including bone mineral density (BMD), total 25-hydroxyvitamin D (T25(OH)D) levels and calcium supplementation to investigate the causal relationship between PCSK9 inhibitors and osteoporosis. The LDL-C level was chosen as the exposure variable in a sample size of 173,082 individuals. We conducted a MR analysis on the relationship between PCSK9 inhibitors and osteoporosis, elucidating the mediators involved. Utilizing the inverse variance weighted (IVW) method, we found the risk of osteoporosis was reduced by 0.6% in those who used PCSK9 inhibitors compared with non-users (OR: 0.994, 95%CI: 0.991-0.998, P < 0.001). In people aged 30-45 years, the risk of low BMD was 1.176 times higher among PCSK9 inhibitor users compared to non-users (OR: 1.176, 95%CI: 1.017-1.336, P = 0.045). Conversely, people aged 45-60 years who used PCSK9 inhibitors had a 14.9% lower risk of low BMD compared to non-users (OR: 0.851, 95%CI: 0.732-0.968, P = 0.007). Mediation analysis revealed that 43.33% of the impact of PCSK9 inhibitors on osteoporosis was mediated through BMD levels, with the remaining 56.67% being a direct effect. Effects of PCSK9 inhibitors on BMD levels varied in different ages. In addition, the risk of high serum T25(OH)D levels were 1.091 times among PCSK9 inhibitor users compared to non-users (OR: 1.091, 95%CI: 1.065-1.112, P < 0.001), providing valuable insights for clinicians.

Development and assessment of a predictive model for early diagnosis of rheumatoid arthritis in southwest China: A new nomogram.

Rheumatoid arthritis (RA) is a disease complicated with inflammatory synovitis, which seriously affects the life quality of patients. Early diagnosis is important for prognosis of RA. Here, we aimed to develop and assess a model for early diagnosis of RA in southwest China. A nomogram including 44 patients with an early diagnosis of RA was developed. Variables were filtered by least absolute contraction selection operator and multiple logistic regression. The efficiency and clinical application range were evaluated. This nomogram showed that rheumatoid factor, erythrocyte sedimentation rate, RA33, facet joint and knee joint had high positive predictive value for RA. The area under curve was 0.920 [95% confidence interval (CI): 0.865-0.975]. In the validation model, area under curve was 0.942 (95% CI: 0.893-0.991). Calibration and decision curve suggested that this nomogram was helpful within the threshold probability range of 0.02 to 1.00. Using this nomogram will help clinicians in the early diagnosis of RA. Laboratory indicators such as rheumatoid factor, erythrocyte sedimentation rate, RA33, and clinical symptoms such as morning stiffness, facet joint and knee joint are very important, which deserves the attention of clinicians.

Causality between depression and ankylosing spondylitis in a European population: Results from a Mendelian randomization analysis.

The aim of this study was to explore the application of Mendelian randomization (MR) Egger and inverse variance weighted (IVW) in a causal effect on depression and ankylosing spondylitis (AS). Instrumental variables (IVs) were determined using genome-wide association studies. The 2-sample MR analysis was conducted by MR Egger to test the causal effect between depression and AS. The pleiotropy of potential instrumental variables was evaluated. The results of MR Egger and IVW were further compared. A total of 3 single nucleotide polymorphisms as the construct IVs were included. IVW results showed a significant causal effect between depression and AS (P < .001). Depression could promote the risk of AS (odds ratio = 1.060, 95% confidence interval: 1.026-1.094). However, the MR Egger showed no causal effect (P = .311). Heterogeneity statistics suggested that no heterogeneity was existed (P > .05). It was also suggested that there was no horizontal pleiotropy in IVs (MR Egger intercept: -0.0004, P = .471). Reverse MR analysis suggested that there was no causal effect between AS and depression (P > .05). Gene expression quantitative trait locus (QTLs) suggested that rs2517601 and RNF39 were positively correlated (beta = 1.066, P < .001). Depression may be one of the causes of AS by MR analysis in a European population. We can estimate the causal effect based on IVW when horizontal pleiotropy is very tiny.

Uncovering potential new biomarkers and immune infiltration characteristics in primary Sjögren's syndrome by integrated bioinformatics analysis.

Primary Sjögren's syndrome (pSS) is known as autoimmune disease characterized by damage to endocrine glands, such as the salivary and lacrimal glands. This study aimed to identify potential biomarkers for pSS using integrated bioinformatics analysis and explore the relationship between differentially expressed genes (DEGs) and immune infiltration. Three pSS datasets (GSE7451, GSE23117, and GSE40611) from the gene expression omnibus database were integrated. All the datasets were processed in R (version 4.0.3). A total of 16 immune cells and 13 immune functions were obtained. The top immune cell and immune function were "activated" dendritic cells and major histocompatibility complex class I. Correlation analysis showed the top correlation among 16 immune cells were B cells and tumor infiltrating lymphocytes, check-point and T cell co-stimulation, respectively. In comparisons of immune score, "activated" dendritic cells (.657 vs 594, P < .001), B cells (.492 vs 434, P = .004), macrophages (.631 vs 601, P = .010), inflammation-promoting (.545 vs 478, P < .001), Type I interferon Reponse (.728 vs 625, P < .001) and so on were higher in pSS than control group. In correlation analysis, the up-regulation of interferon induced protein with tetratricopeptide repeats 1 gene was strongly correlated with Type I interferon response with a correlation coefficient of .87. The receiver operating characteristic curve of 5 genes showed that the area under curve was.891. In the verification model, the area under curve was.881. In addition, disease ontology analysis supported the association between DEGs and pSS. In summary, pSS has a variety of DEGs in immune infiltration, which is worthy of the attention from clinicians.

Early treatment of rituximab combined with eltrombopag for secondary thrombocytopenic purpura in rheumatoid arthritis: A case report.

RATIONALE: Secondary immune thrombocytopenic purpura (ITP) is also known as acquired thrombocytopenic purpura, autoimmune disease is usually one of the important causes. There are few reports about treatment of refractory thrombocytopenic purpura in rheumatoid arthritis (RA). We report a case of refractory ITP in which changes in platelet-related markers with therapeutic agents are worthy of the attention of clinicians. PATIENT CONCERNS: A 69-year-old woman admitted for ecchymosis on the neck and arms for 15 days presented to our hospital. She was diagnosed with RA 5 years ago. DIAGNOSIS: The diagnosis met the American College of Rheumatology/European League Against Rheumatism 2010 classification criteria. The disease activity score 28 (DAS-28) was 4.6, indicating that the disease activity was moderate. INTERVENTIONS: Treatment with first-line therapies and second-line treatment--eltrombopag (EPAG) were ineffective. Therefore, we performed rituximab combined with a low dose of EPAG. OUTCOMES: The patient received 2 cycles of rituximab combined with EPAG, and reported no new petechiae on her buccal mucosa and limbs during follow-up. LESSONS: This case suggests that early treatment of rituximab combined with EPAG is beneficial to patients with refractory ITP in RA. In terms of disease dynamic monitoring, immature platelet fraction (IPF) may be an auxiliary indicator for predicting efficacy, but its significance needs further study.

Clinical significance of HEp-2 cell cytoplasmic patterns in anti-neutrophil cytoplasmic antibody associated vasculitis.

ABSTRACT: The study was to investigate the clinical characteristics and significance of antinuclear antibody (ANA) cytoplasmic patterns in ANCA-associated vasculitis (AAV) from Southwest China.A retrospective study including 232 AAV patients from Peoples Hospital of Deyang City was performed. These included 115 patients with ANA cytoplasmic pattern as observation group and 117 patients without ANA cytoplasmic pattern as control group.Chest involvement (60.00 vs 46.15, P = .035), cardiovascular involvement (5.21 vs 29.91, P < .001), and renal involvement (37.39 vs 77.78, P = .001) were different between groups.Total protein (69.55 vs 64.01, P < .001), triglyceride (1.41 vs 1.18, P = .023), mean cell volume (89.76 vs 87.59, P = .040), and estimated glomerular filtration rate (76.67 vs 50.87, P = .035) were higher in ANA cytoplasmic patterns group. Creatinine (73.00 vs 117.50, P = .011), white blood cell (6.93 vs 8.86, P = .001), platelet (196.0 vs 239.0, P = .017), anti-myeloperoxidase (2.44 vs 3.42, P = .042), and anti-proteinase 3 (1.00 vs 4.93, P = .007) were lower in this group. In multivariate analysis, creatinine (odds ratio [OR] = 1.21, 95% confidence interval [CI]: 1.06-1.38), triglyceride (OR = 1.97, 95% CI: 1.10-3.48), and anti-myeloperoxidase (OR = 1.64, 95% CI: 1.37-1.95) were independent risk factors of AAV renal involvement. Total protein (OR = .95, 95% CI: 0.91-0.99) was an independent protective factor of AAV renal involvement. Chi-square test showed that speckled pattern was different among anti-neutrophil cytoplasmic antibody patterns (χ2 = 18.526, P < .001).In summary, HEp-2 cell cytoplasmic patterns have certain clinical significance in AAV, which is a new exploration of the clinical value of ANA.

Predicting bacterial infection risk in patients with ANCA-associated vasculitis in southwest China: development of a new nomogram.

OBJECTIVES: The aim of this study was to develop and assess a risk nomogram of bacterial infection in patients with ANCA-associated vasculitis (AAV) in southwest China. METHOD: We established a prediction model based on a training dataset of 249 AAV patients. The least absolute shrinkage and selection operator (Lasso) was used to screen feature variables. Multivariate logistic regression analysis was used to build a prediction model for feature variables. Nomogram was used to predict the risk of bacterial infection in AAV patients. Receiver operating characteristic (ROC) curve was used to evaluate and verify the prediction accuracy of the model. Calibration and clinical useful range was assessed using calibration curve and decision curve analysis, respectively. RESULTS: Bactericidal permeability enhancement protein of ANCAs (BPI-ANCAs), procalcitonin (PCT), and white blood cell (WBC) were the characteristic variables in this study. Nomogram showed that positive BPI-ANCAs and PCT had higher positive predictive value for bacterial infection in AAV patients. The area under curve (AUC) of the model was 0.703 (95% confidence interval: 0.640-0.766). In the validation model, the AUC was 0.745 (95% confidence interval: 0.617-0.872). Decision curve analysis showed that the nonadherence nomogram was clinically useful within the threshold probability range of 0.31-0.85. CONCLUSIONS: Nomogram combined with BPI-ANCAs and PCT has the guiding significance for predicting bacterial infection risk in AAV. As an ANCA-specific autoantibody, BPI-ANCAs is helpful for clinicians to understand the role of specific autoantibodies in the pathogenesis of AAV. Key Points • BPI-ANCAs, PCT, and WBC could predict bacterial infection in AAV patients. • Nomogram showed that positive BPI-ANCAs had a high positive predictive value for bacterial infection in AAV patients.

Bioinformatics analysis identified immune infiltration, risk and drug prediction models of copper-induced death genes involved in salivary glands damage of primary Sjögren's syndrome.

This study aimed to identify copper-induced death genes in primary Sjögren's syndrome (pSS) and explore immune infiltration, risk and drug prediction models for salivary glands (SGs) damage. The 3 datasets, including GSE40611, GSE23117, and GSE7451 from the Gene Expression Omnibus database were downloaded. The datasets were processed using the affy in R (version 4.0.3). In immune cells, copper-induced death genes were strongly expressed in "activated" dendritic cells (aDCs), macrophages and regulatory T cells (Treg). In immune functions, copper-induced death genes were strongly expressed in major histocompatibility complex (MHC) class I, human leukocyte antigen (HLA) and type I interferon (IFN) response. Correlation analysis showed that 5 genes including SLC31A1, PDHA1, DLD, ATP7B, and ATP7A were significantly correlated with immune infiltration. The nomogram suggested that the low expression of PDHA1 was significant for predicting the risk of pSS and the area under curve was 0.678. Drug model suggested that "Bathocuproine disulfonate CTD 00001350," "Vitinoin CTD 00007069," and "Resveratrol CTD 00002483" were the drugs most strongly associated with copper-induced death genes. In summary, copper-induced death genes are associated with SGs injury in pSS, which is worthy of clinicians' attention.

The value of anti-rods and rings antibodies in patients with nonhepatitis virus infection: A single-center retrospective study from Southwest China.

ABSTRACT: The aim of this study was to retrospectively investigate the clinical significance of anti-rods and rings (anti-RR) antibodies in nonhepatitis virus infection patients from Southwest China.Anti-RR antibodies were determined by indirect immunofluorescence assay in a group of 19,935 individuals with antinuclear antibodies test from January 2017 to December 2019. The laboratory and clinical data were collected. Finally, 66 samples with anti-RR antibodies (0.33%) were detected.In Wilcoxon rank sum test, gamma glutamyl transferase (Z = -3.364, P = .001), alpha-l-fucosidase (AFU) (Z = -2.312, P = .021), uric acid (Z = -1.634, P = .047) and red blood cell distribution width (Z = -2.285, P = .022) were higher in metabolic disease group than nonmetabolic disease group. In independent-samples t test, endogenous creatinine clearance was higher in metabolic disease group than nonmetabolic disease group (t = 2.061, P = .045). During the follow-up period of 37 patients with anti-RR antibodies for 1 to 60 months, the titers of anti-RR were significantly increased in the metabolic disease group (Z = -2.346, P = .019). In binary logistic regression analysis, triglycerides (odds ratio 3.679, 95% confidence interval 1.467-24.779, P = .048) was associated with elevated titers of anti-RR antibodies.In summary, anti-RR in non-hepatitis patients may be a manifestation of metabolic disorders, and has a certain correlation with routine laboratory indicators, which is worthy of the attention from clinicians.

Clinical significance and influencing factors of fibrinogen in ANCA-associated vasculitis: A single-center retrospective study from Southwest China.

Hypercoagulable is an important pathological state in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). Fibrinogen (FIB) is the main protein in coagulation process. In this study, we aimed to investigate the clinical significance and influencing factors of FIB in AAV from Southwest China.A retrospective study was performed on AAV patients from Peoples Hospital of Deyang City from January 2007 to December 2018. Demographic and clinical characteristics were collected.A total of 463 AAV patients were included. In Wilcoxon rank sum test, FIB was significantly higher in AAV active group than inactive group (P = .005). FIB was also higher in bacterial infection group than in non-infection group both in active group (P = .008) and inactive group (P = .017). In receiver operating characteristic (ROC) curve analysis, the critical value of FIB for diagnosis of bacterial infection between AAV active and inactive groups was 3.385 g/L (P = .030), with sensitivity of 70.2% and specificity of 52.9%. In the multivariate analysis of variance (MANOVA), estimated glomerular filtration rate (eGFR) was shown to be an independent factor for FIB (P = .001). Least-significant difference showed the concentration of FIB (P < .05) increased with renal impairment, especially in endstage kidney disease (ESKD).FIB identified a certain reference value in distinguishing AAV activity from bacterial infection. ESKD had a statistical effect on it. Influencing factors of FIB should be evaluated based on the renal function impairment of patients.