Prescription glucocorticoid medication and iridocyclitis are associated with an increased risk of senile cataract occurrence: a Mendelian randomization study.

Iridocyclitis and the use of glucocorticoid medication have been widely studied as susceptibility factors for cataracts. However, the causal relationship between them remains unclear. This study aimed to investigate the causal relationship between the development of iridocyclitis and the genetic liability of glucocorticoid medication use on the risk of senile cataracts occurrence by performing Two-sample Mendelian randomization (MR) analyses. Instrumental variables (IVs) significantly associated with exposure factors (P < 5 × 10-8) were identified using published genome-wide association data from the FinnGen database and UK Biobank. Reliability analyses were conducted using five approaches, including inverse-variance weighted (IVW), MR-Egger regression, simple median, weighted median, and weighted mode. A sensitivity analysis using the leave-one-out method was also performed. Genetic susceptibility to glucocorticoid use was associated with an increased risk of developing senile cataracts (OR, 1.10; 95% CI, 1.02-1.17; P < 0.05). Moreover, iridocyclitis was significantly associated with a higher risk of developing senile cataracts (OR, 1.03; 95% CI, 1.01-1.05; P < 0.05). Nonetheless, some heterogeneity in the IVs was observed, but the MR results remained consistent after penalizing for outliers. The estimates were consistent in multivariate analyses by adjusting for body mass index (BMI) and diabetes mellitus type 2 (T2DM). This study provides new insights into the prevention and management of senile cataracts by highlighting the increased risk associated with iridocyclitis and the use of glucocorticoids.

The efficacy and safety of short-term and low-dose IL-2 combined with tocilizumab to treat rheumatoid arthritis.

Background: Immunotherapy targeting factors related to immune imbalance has been widely employed for RA treatment. This study aimed to evaluate the efficacy and safety of low-dose interleukin (IL)-2 combined with tocilizumab (TCZ), a biologics targeting IL-6, in RA patients. Methods: Fifty adults with active RA who met the criteria with complete clinical data were recruited, and divided into three groups: control group (n=15), IL-2 group (n=26), and IL-2+TCZ group (n=9). In addition to basic treatment, participants in the IL-2 group received IL-2 (0.5 MIU/day), while participants in the IL-2+TCZ group received IL-2 (0.5 MIU/day) along with one dose of TCZ (8 mg/kg, maximum dose: 800 mg). All subjects underwent condition assessment, laboratory indicators and safety indicators detection, and records before treatment and one week after treatment. Results: Compared with the baseline, all three groups showed significant improvement in disease conditions, as evidenced by significantly reduced disease activity indicators. The low-dose IL-2 and combination treatment groups demonstrated a violent proliferation of Tregs, while the absolute number of Th1, Th2, and Th17 cells in the latter group showed a decreasing trend. The decrease in the Th17/Treg ratio was more pronounced in the IL-2+TCZ groups. No significant adverse reactions were observed in any of the patients. Conclusion: Exogenous low doses of IL-2 combined TCZ were found to be safe and effective in reducing effector T cells and appropriately increasing Treg levels in RA patients with high effector T cell levels. This approach helps regulate immune homeostasis and contributes to the prevention of disease deterioration. Clinical trial registration: https://www.chictr.org.cn/showprojEN.html?proj=13909, identifier ChiCTR-INR-16009546.

Genetic evidence reveals a causal relationship between rheumatoid arthritis and interstitial lung disease.

Background/purpose: Previous epidemiological studies have associated interstitial lung disease (ILD) with rheumatoid arthritis (RA), yet the causality of this relationship remains uncertain. This study aimed to investigate the genetic causal link between ILD and RA. Methods: Genome-wide association study (GWAS) statistics for ILD and RA were collected from public datasets. Relevant single-nucleotide polymorphisms (SNPs) were selected by executing quality control steps from the GWAS summary results. A two-sample bidirectional Mendelian randomization (MR) analysis was performed to assess the causal relationship between the two conditions. The MR analysis primarily used the inverse variance weighting (IVW), weighted median (WM), and MR-Egger regression methods. Sensitivity analyses, including MR-Egger, leave-one-out, and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), were conducted to evaluate the heterogeneity and pleiotropy. Replication analyses using Asian datasets were also conducted to enhance the robustness of our findings. Results: In the European population, RA was found to increase the risk of ILD by 9.6% (OR: 1.096, 95% CI: 1.023-1.174, p = 0.009). Conversely, ILD was associated with a 12.8% increased risk of RA (OR: 1.128, 95% CI: 1.013-1.256, p = 0.029). Replication analyses from Asian GWAS further supported these findings, particularly the increased risk of ILD attributable to RA (OR: 1.33, 95% CI: 1.18-1.49, p-value <0.001). Conclusion: Our findings underscore the clinical importance of screening for ILD in RA patients and suggest that effective management of RA could significantly benefit ILD patients. The potential applicability of novel RA treatments to ILD warrants further exploration. Additionally, racial disparities in the manifestation of these diseases should not be overlooked, as they may offer new perspectives for targeted therapies in diverse populations.

Efficacy and safety of bimekizumab in the treatment of psoriatic arthritis: a systematic review and meta-analysis.

BACKGROUND: Bimekizumab, a humanized monoclonal IgG1 antibody targeting both interleukin (IL)-17A and IL-17F, could be effective for treating Psoriatic arthritis (PsA). This study aimed to systematically evaluate the efficacy and safety of bimekizumab in the management of PsA. RESEARCH DESIGN AND METHODS: A comprehensive literature search by August 2023 was performed through PubMed, Embase, Cochrane Controlled Register of Trials, and ClinicalTrials.gov. investigating the efficacy or safety data of bimekizumab in the treatment of PsA. Data was pooled using the random-effects models. Egger tests were used to evaluate potential publication bias. RESULTS: A total of 4 RCTs, involving 892 PsA patients and 467 placebo controls, were included in this analysis. Bimekizumab significantly increased the rates of PASI75 and PASI100 compared with placebos [RR = 7.22, 95% CI (5.24, 9.94), p < 0.001; RR = 10.12, 95% CI (6.00, 17.09), p < 0.001]. The rate of overall adverse events was slightly higher in the bimekizumab group [RR = 1.42, 95% CI (1.05, 1.93) p = 0.023). However, there were fewer adverse severe drug reactions in the bimekizumab group compared to the placebo. CONCLUSION: Bimekizumab had a significant clinical benefit in managing PsA and an acceptable safety profile.

Genetically determined type 1 diabetes mellitus and risk of osteoporosis.

BACKGROUND: Observational evidence suggests that type 1 diabetes mellitus (T1DM) is associated with the risk of osteoporosis (OP). Nevertheless, it is not apparent whether these correlations indicate a causal relationship. To elucidate the causal relationship, a two-sample Mendelian randomization (MR) analysis was performed. METHODS: T1DM data was obtained from the large genome-wide association study (GWAS), in which 6683 cases and 12,173 controls from 12 European cohorts were involved. Bone mineral density (BMD) samples at four sites were extracted from the GEnetic Factors for OSteoporosis (GEFOS) consortium, including forearm (FA) (n = 8,143), femoral neck (FN) (n = 32,735), lumbar spine (LS) (n = 28,498), and heel (eBMD) (n = 426,824). The former three samples were from mixed populations and the last one was from European. Inverse variance weighting, MR-Egger, and weighted median tests were used to test the causal relationship between T1DM and OP. A series of sensitivity analyses were then conducted to verify the robustness of the results. RESULTS: Twenty-three independent SNPs were associated with FN-BMD and LS-BMD, twenty-seven were associated with FA-BMD, and thirty-one were associated with eBMD. Inverse variance-weighted estimates indicated a causal effect of T1DM on FN-BMD (odds ratio (OR) =1.033, 95 % confidence interval (CI): 1.012-1.054, p = 0.002) and LS-BMD (OR = 1.032, 95 % CI: 1.005-1.060, p = 0.022) on OP risk. Other MR methods, including weighted median and MR-Egger, calculated consistent trends. While no significant causation was found between T1DM and the other sites (FA-BMD: OR = 1.008, 95 % CI: 0.975-1.043, p = 0.632; eBMD: OR = 0.993, 95 % CI: 0.985-1.001, p = 0.106). No significant heterogeneity (except for eBMD) or horizontal pleiotropy was found for instrumental variables, suggesting these results were reliable and robust. CONCLUSIONS: This study shows a causal relationship between T1DM and the risk of some sites of OP (FN-BMD, LS-BMD), allowing for continued research to discover the clinical and experimental mechanisms of T1DM and OP. It also contributes to the recommendation if patients with T1DM need targeted care to promote bone health and timely prevention of osteoporosis.

Genetic prediction of modifiable lifestyle factors for erectile dysfunction.

Background: The causal relationship between certain lifestyle factors and erectile dysfunction (ED) is still uncertain. Aim: The study sought to investigate the causal effect of 9 life factors on ED through 2-sample single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR). Methods: Genetic instruments to proxy 9 risk factors were identified by genome-wide association studies. The genome-wide association studies estimated the connection of these genetic variants with ED risk (n = 223 805). We conducted SVMR, inverse variance-weighting, Cochran's Q, weighted median, MR-Egger, MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier), and MVMR analyses to explore the total and direct relationship between life factors and ED. Outcomes: The primary outcome was defined as self or physician-reported ED, or using oral ED medication, or a history of surgery related to ED. Results: In SVMR analyses, suggestive associations with increased the risk of ED were noted for ever smoked (odds ratio [OR], 5.894; 95% confidence interval [CI], 0.469 to 3.079; P = .008), alcohol consumption (OR, 1.495; 95% CI, 0.044 to 0.760; P = .028) and body mass index (BMI) (OR, 1.177; 95% CI, 0.057 to 0.268; P = .003). Earlier age at first intercourse was significantly related to reduced ED risk (OR, 0.659; 95% CI, -0.592 to -0.244; P = 2.5 × 10-6). No strong evidence was found for the effect of coffee intake, time spent driving, physical activity, and leisure sedentary behaviors on the incidence of ED (All P > .05). The result of MVMR analysis for BMI (OR, 1.13; 95% CI, 1.01 to 1.25; P = .045) and earlier age at first intercourse (OR, 0.77; 95% CI, 0.56 to 0.99; P = .018) provided suggestive evidence for the direct impact on ED, while no causal factor was detected for alcoholic drinks per week and ever smoked. Clinical implications: This study provides evidence for the impact of certain modifiable lifestyle factors on the development of ED. Strengths and limitations: We performed both SVMR and MVMR to strengthen the causal relationship between exposures and outcomes. However, the population in this study was limited to European ancestry. Conclusion: Ever smoked, alcoholic drinks per week, BMI, and age first had sexual intercourse were causally related to ED, while the potential connection between coffee intake, physical activity, recreational sedentary habits, and increased risk of ED needs to be further confirmed.

Exploring the therapeutic potential of regulatory T cell in rheumatoid arthritis: Insights into subsets, markers, and signaling pathways.

Rheumatoid arthritis (RA) is a complex autoimmune inflammatory rheumatic disease characterized by an imbalance between immunological reactivity and immune tolerance. Regulatory T cells (Tregs), which play a crucial role in controlling ongoing autoimmunity and maintaining peripheral tolerance, have shown great potential for the treatment of autoimmune inflammatory rheumatic diseases such as RA. This review aims to provide an updated summary of the latest insights into Treg-targeting techniques in RA. We focus on current therapeutic strategies for targeting Tregs based on discussing their subsets, surface markers, suppressive function, and signaling pathways in RA.

Efficacy and Safety of Risankizumab in Patients with Psoriatic Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Currently, the cause of psoriatic arthritis (PsA) is unknown, and the effectiveness of current drug treatments is unsatisfactory. In March 2019, the US Food and Drug Administration (FDA) approved risankizumab, a humanized immunoglobulin G1 (IgG1) monoclonal antibody targeting the p19 subunit of interleukin (IL)-23, for the treatment of PsA in adults. This study aimed to conduct a meta-analysis of double-blind, randomized, placebo-controlled trials to evaluate the effectiveness and safety of risankizumab in moderate-to-severe PsA. METHODS: We conducted a thorough search of relevant databases from the establishment of the databases to October 1, 2023. We conducted a meta-analysis using Stata 12.0 and utilized I2 and Egger tests to assess heterogeneity and publication bias among the studies. Bias assessment was performed using the risk bias map and bias risk summary diagram generated by Revman5.4 software. The review protocols were registered on PROSPERO (CRD42023451894) and adhered to the preferred reporting item of system evaluation (PRISMA) guideline. RESULTS: Six randomized controlled trials (RCTs) involving 5038 patients with PsA treated with either risankizumab or placebo were included in the analysis. At 24 weeks, the risankizumab group demonstrated a significantly higher American College of Rheumatology-20 (ACR20) response rate compared to the placebo group (RR 1.760, 95% CI 1.568-1.977, P < 0.001). Additionally, the risankizumab group showed a significantly higher Minimal Disease Activity (MDA) response rate compared to the placebo group (RR 1.827, 95% CI 1.048-3.184, P < 0.05). The risankizumab group also exhibited improvement in Short Form 36 Questionnaire (SF-36) score (SMD 0.51, 95% CI 0.33-0.69, P < 0.001), with significantly lower Health Assessment Questionnaire Disability Index (HAQ-DI) score (SMD - 0.27, 95% CI - 0.37 to - 0.17, P < 0.001) and higher Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score (SMD 0.27, 95% CI 0.20-0.35, P < 0.001) compared to the placebo group. Moreover, the risankizumab group had a significantly lower Psoriasis Area and Severity Index (PASI) score (SMD - 6.12, 95% CI - 10.02 to 2.23, P < 0.001). A study by Mease et al. indicated that patients receiving risankizumab generally demonstrated numerical improvements in the Leeds Enthesitis Index (LEI), although the small sample size limits the evidence. Further research is necessary to provide evidence-based guidelines. There were no significant differences in the incidence of serious adverse events (SAE) and serious treatment-emergent adverse events (STEAE) between the risankizumab and placebo groups (RR 0.76, 95% CI 0.45-1.28, P = 0.31; RR 0.99, 95% CI 0.49-1.99, P = 0.97, respectively), and the overall incidence of adverse events (AE) was not comparable (RR 1.10, 95% CI 0.63-1.94, P = 0.73). CONCLUSION: Risankizumab showed superior efficacy across multiple outcome measures compared to placebo, with no significant increase in adverse events. Our findings endorse risankizumab as an excellent treatment option for PsA, offering valuable insights for clinicians and patients when choosing appropriate therapeutic interventions. TRIAL REGISTRATION: Retrospectively registered (CRD42023451894, 16 August 2023).

Dysbiosis of the Gut Microbiota in Patients with Psoriatic Arthritis is Closely Related to Lymphocyte Subsets and Cytokines.

The purpose of this research was to characterize the microbiota of patients with psoriatic arthritis (PsA) and to compare the relationship between the microbiota and peripheral lymphocyte subsets and cytokines. We collected stool samples from 13 PsA patients and 26 sex- and age-matched healthy controls (HCs) and researched the gut microbiota by sequencing the V3-V4 variable region of the bacterial 16S rRNA gene with the Illumina Miseq PE300 system. Flow cytometry was used to assess the peripheral lymphocyte subsets in these participants. Record measures of disease activity such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Alpha and beta diversity were assessed using results from QIIME2. Panel demonstrated the average relative abundance of the different genera in PsA and HCs. Correlation between clinical parameters and the relative abundance of the genus in samples was assessed by the Pearson correlation analysis using R (version 4.0.1). Compared with HC, the abundance of gut microbiota (Chao 1 and ACE) decreased in patients with PsA, and the diversity of bacteria (Shannon and Simpson indices) also decreased in PsA (Fig. 1a). ß Diversity analysis indicated differences in microbial communities between PsA and HC (Fig. 1b, r = 0.039, p = 0.264, ANOSIM). Furthermore, 18 bacterial groups were significantly different at the genus level in PsA compared to HCs (p < 0.05) (Fig. 2).In the phylum and genus, lymphocyte subsets and cytokines are associated with the microbiota. The gut microbiota of patients with PsA differs from HC, which was closely related to lymphocyte subsets.

Efficacy, safety and the lymphocyte subsets changes of low-dose IL-2 in patients with systemic lupus erythematosus: A systematic review and meta-analysis.

INTRODUCTION: Existing therapies of systemic lupus erythematosus (SLE) are efficacious only in certain patients. Developing new treatment methods is urgent. This meta-analysis aimed to evaluate the efficacy and safety of low-dose IL-2 (LD-IL-2). METHODS: According to published data from PubMed, Web of Science, Embase, ClinicalTrials.gov, MEDLINE, MEDLINE, Web of Knowledge, Cochrane Library, and FDA.gov, eight trials were included. RESULTS: After the LD-IL-2 treatment, 54.8% of patients had distinct clinical remission. The SRI-4 response rates were 0.819 (95% confidence interval [CI]: 0.745-0.894), and the SELENA-SLEDAI scores were significantly decreased (SMD = -2.109, 95% CI: [-3.271, -0.947], p < .001). Besides, the proportions of CD4+ T (SMD = 0.614, 95% CI: [0.250, 0.979], p = .001) and Treg cells (SMD = 1.096, 95% CI: [0.544, 1.649], p < .001) were increased dramatically after LD-IL-2 treatment, while there were no statistical differences in the proportions of CD8+ T cells, Th1 cells, Th2 cells, and Th17 cells (p > .05). Besides, the proportions of Th17 (SMD = 1.121, 95% CI: [0.709, 1.533], p < .001) and Treg (SMD = 0.655, 95% CI: [0.273, 1.038], p = .001) were significantly increased after receiving subcutaneously 0.5 million IU of LD-IL-2 treatment per day for 5 days, but there were no statistical differences in the proportions of Treg after receiving 1 million IU every other day subcutaneously of LD-IL-2 treatment. Injection site reaction and fever were common side effects of IL-2, which occurred in 33.1% and 14.4% of patients. No serious adverse events were reported. CONCLUSION: LD-IL-2 was promising and well-tolerated in treating SLE, which could promote Treg's proliferation and functional recovery. Injecting 0.5 million IU of IL-2 daily can better induce the differentiation of Treg cells and maintain immune homeostasis than injecting 1 million IU every other day.

Study on the expression changes of lncRNA in patients with systemic lupus erythematosus and its correlation with Treg cells.

OBJECTIVES: We initially explored the link between the differentially expressed long non-coding RNAs (lncRNAs) and the number of regulatory T (Treg) cells by detecting the lncRNA expression profiles in patients with systemic lupus erythematosus (SLE), then analyzed the correlation between Treg-related lncRNAs and the clinical features of SLE patients, predicting the mechanism by which lncRNAs regulate the differentiation and development of Treg cells, and provided new ideas for the treatment of SLE. METHODS: Peripheral blood of 9 active SLE patients were collected and mononuclear cells (PBMCs) were extracted; the lncRNA expression profiles of PBMCs were analyzed by whole transcriptome sequencing. Nine healthy people were used as controls to screen the differentially expressed lncRNAs, to analyze the correlation between lncRNAs and Treg cell number. Pearson test was used to analyze the correlation between lncRNAs and the number of Treg cell, and the correlation between Treg-associated lncRNA and SLEDAI score, ESR, C3, and C4 in SLE patients. The targeted genes of Treg-associated lncRNAs were predicted with miRcode and Targetscan databases and coexpression network. RESULTS: There were 240 differentially expressed lncRNAs in SLE patients compared with healthy controls, including 134 highly expressed lncRNAs (p < 0.05) and 106 lowly expressed lncRNAs (p < 0.05). The expression of ANKRD44-AS1 (r = 0.7417, p = 0.0222), LINC00200 (r = 0.6960, p = 0.0373), AP001363.2 (r = 0.7766, p = 0.0138), and LINC02824 (r = 0.7893, p = 0.0114) were positively correlated with the number of Treg cell, and the expression of AP000640.1 (r = - 0.7225, p = 0.0279), AC124248.1 (r = - 0.7653, p = 0.0163), LINC00482 (r = - 0.8317, p = 0.0054), and MIR503HG (r = - 0.7617, p < 0.05) were negatively correlated with the number of Treg cell. Among these Treg-associated lncRNAs, the expression of LINC00482 (r = - 0.7348, p < 0.05) and MIR503 HG (r = - 0.7617, p < 0.05) were negatively correlated with C3. LINC00200, ANKRD44 - AS1, and AP000640.1 related to Treg cells regulate the expression of signal transducer and activator of transcription 5 (STAT5), phospholipase D1 (PLD1), homeodomain-only protein X (HOPX), and runt-related transcription factor 3 (RUNX3) through competitive binding of miRNA or trans-regulatory mechanism, thereby regulating the differentiation and development of Treg cell. CONCLUSIONS: The lncRNA expression profiles were changed in SLE patients, the differentially expressed lncRNAs were associated with abnormal number and function of Treg cells in SLE, and Treg-associated lncRNAs were associated with SLE-disease activity, which may affect the expression of STAT5, PLD1, HOPX, RUNX3 and regulate Treg cell function and participate in the pathogenesis and progression of SLE by competitively binding to miRNAs or trans-regulatory mechanism. Key points • Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple organs and systems. lncRNAs may affect Treg cells function by regulating genes expression, which may be an important pathogenesis of SLE. • This study, taking SLE as an example, preliminarily analyzed the correlation between lncRNA and Treg cells in SLE patients, analyzed the correlation between Treg-related lncRNA and the clinical characteristics of SLE, and speculated that lncRNA could regulate the differentiation and development of Treg cells through competitive combination with miRNA or trans-regulatory mechanisms. • It is possible to target epigenetic therapy for SLE.

Efficacy, Safety and the Lymphocyte Subset Changes of Low-Dose IL-2 in Patients with Autoimmune Rheumatic Diseases: A Systematic Review and Meta-Analysis.

INTRODUCTION: Current therapies for autoimmune rheumatic diseases (ARDs) have limited efficacy in certain patients, highlighting the need for the development of novel treatment approaches. This meta-analysis aims to assess the efficacy and safety of low-dose interleukin-2 (LD-IL-2) and evaluate the alterations in lymphocyte subsets in various rheumatic diseases following administration of different dosages of LD-IL-2. METHODS: A comprehensive search was conducted in PubMed, Web of Science, the Cochrane Library, Embase databases and CNKI to identify relevant studies. A total of 31 trials were included in this meta-analysis. The review protocols were registered on PROSPERO (CRD42022318916), and the study followed the PRISMA guidelines. RESULTS: Following LD-IL-2 treatment, patients with ARDs exhibited a significant increase in the number of Th17 cells and Tregs compared to their pre-treatment levels [standardized mean difference (SMD) = 0.50, 95% confidence interval (CI) (0.33, 0.67), P < 0.001; SMD = 1.13, 95% CI (0.97, 1.29), P < 0.001]. Moreover, the Th17/Tregs ratio showed a significant decrease [SMD = - 0.54, 95% CI (- 0.64, - 0.45), P < 0.001]. In patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), LD-IL-2 injection led to a significant increase in Treg numbers, and the Th17/Tregs ratio and disease activity scores, including Disease Activity Score-28 joints (DAS28), Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) and Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), were all significantly reduced. No serious adverse events were reported in any of the included studies. Additionally, 54.8% of patients with lupus nephritis achieved distinct clinical remission following LD-IL-2 treatment. Injection site reactions and fever were the most common side effects of LD-IL-2, occurring in 33.1% and 14.4% of patients, respectively. CONCLUSION: LD-IL-2 treatment showed promise and was well tolerated in the management of ARDs, as it effectively promoted the proliferation and functional recovery of Tregs. TRIAL REGISTRATION: Retrospectively registered (CRD42022318916, 21/04/2022).

Genetic association between interleukin-17 and susceptibility to rheumatoid arthritis.

BACKGROUND: The pathogenesis of rheumatoid arthritis (RA) is an immune imbalance, in which various inflammatory immune cells and pro-inflammatory factors are involved. Interleukin-17 (IL-17), a potent pro-inflammatory cytokine, has been found to have increased expression in the joints of patients with RA compared to healthy individuals. However, the causal relationship between the expression level of IL-17 or IL-17 receptor (IL-17R) and RA remained unknown. In this study, two-sample Mendelian randomization (MR) was used to investigate the causal relationship between IL-17 and RA. METHODS: Summary statistics for RA (14,361 RA cases and 43,923 healthy controls) and IL-17 (3,301 samples) were obtained from an available meta-analysis of published genome-wide association studies (GWAS). Relevant single nucleotide polymorphisms (SNPs) were selected by executing quality control steps from the GWAS summary results. Then we used bi-directional two-sample Mendelian randomization (MR) and multi-variable MR (MVMR) analysis to examine evidence of causality. MR and MVMR analyses progressed mainly using inverse variance weighted (IVW), weighted median (WM), and MR-Egger regression methods, which were applied to the genetic instrumental variables (IVs) of IL-17A/IL-17 RA, IL-17C/IL-17 RC, and IL-17D/IL-17RD and RA. For assessing the robustness of the results, we also carried out a sensitivity analysis to assess heterogeneity and pleiotropy, such as MR-Egger, leave-one-out, and MR pleiotropy residual sum and outlier (MR-PRESSO). RESULTS: Two-sample MR Analysis showed the causal relationship between IL-17A/IL-17RA and RA. The presence of genetically high IL-17A/IL-17RA may increase the risk of RA (IL-17A(OR = 1.095; 95% C.I., 0.990-1.210, p.adj = 0.013), IL-17RA(OR = 1.113, 95%CI = 1.006-1.231, p.adj = 0.006)). However, the results indicated that IL-17C/IL-17RC, and IL-17D/IL-17RD demonstrated no causal impact on RA (IL-17C(OR = 1.007, 95%CI = 0.890-1.139, p.adj = 0.152), IL-17RC(OR = 1.006, 95%CI = 0.904-1.119, p.adj = 0.152), IL-17D(OR = 0.979, 95%CI = 0.843-1.137, p.adj = 0.130), IL-17RD(OR = 0.983, 95%CI = 0.876-1.104, p.adj = 0.129)). Furthermore, MVMR analysis shown that IL-17RA(OR = 1.049, 95% CI: 0.997-1.102, p.adj = 0.014) was associated with increased risk of RA. Sensitivity analysis showed no heterogeneity and pleiotropy, suggesting that the above results were robust and reliable. CONCLUSION: The MR analysis provides evidence that IL-17A/IL-17RA are risk factors for RA. This emphasizes the importance of intervention on IL-17A/IL-17RA in patients with RA. Developing drugs that limit IL-17A may reduce the risk of RA.

Genetic evidence for causal effects of leukocyte counts on risk for rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by the accumulation of leukocytes and inflammatory mediators within the synovial tissue. Leukocyte counts are proposed to play a role in the pathogenesis of RA. However, the causality remains unclear. To investigate the causal relationship between various leukocytes and RA by implementing two-sample univariable Mendelian Randomization (MR) and multivariable MR. MR analysis was performed using respective genome-wide association study (GWAS) summary statistics for the exposure traits (eosinophil counts, neutrophil counts, lymphocyte counts, monocyte counts, basophil counts, and white blood cell counts) and outcome trait (RA). Summary statistics for leukocytes were extracted from the Blood Cell Consortium meta-analysis and INTERVAL studies. Public GWAS information for RA included 14,361 cases and 43,923 controls. Inverse variance weighted, weighted median, MR-Egger regression, MR pleiotropy residual sum and outlier, and multivariable MR analyses were performed in MR analysis. Univariable MR found elevated eosinophil counts (OR 1.580, 95% CI 1.389-2.681, p = 1.30 × 10-7) significantly increased the risk of RA. Multivariable MR further confirmed that eosinophil counts were a risk factor for RA. Increased eosinophils were associated with higher risk of RA. Further elucidations of the causality and mechanisms underlying are likely to identify feasible interventions to promote RA prevention.

Mechanistic target of rapamycin (mTOR): a potential new therapeutic target for rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by systemic synovitis and bone destruction. Proinflammatory cytokines activate pathways of immune-mediated inflammation, which aggravates RA. The mechanistic target of rapamycin (mTOR) signaling pathway associated with RA connects immune and metabolic signals, which regulates immune cell proliferation and differentiation, macrophage polarization and migration, antigen presentation, and synovial cell activation. Therefore, therapy strategies targeting mTOR have become an important direction of current RA treatment research. In the current review, we summarize the biological functions of mTOR, its regulatory effects on inflammation, and the curative effects of mTOR inhibitors in RA, thus providing references for the development of RA therapeutic targets and new drugs.

Distinct molecular subtypes of systemic sclerosis and gene signature with diagnostic capability.

Background: As Systemic Sclerosis (SSc) is a connective tissue ailment that impacts various bodily systems. The study aims to clarify the molecular subtypes of SSc, with the ultimate objective of establishing a diagnostic model that can inform clinical treatment decisions. Methods: Five microarray datasets of SSc were retrieved from the GEO database. To eliminate batch effects, the combat algorithm was applied. Immune cell infiltration was evaluated using the xCell algorithm. The ConsensusClusterPlus algorithm was utilized to identify SSc subtypes. Limma was used to determine differential expression genes (DEGs). GSEA was used to determine pathway enrichment. A support vector machine (SVM), Random Forest(RF), Boruta and LASSO algorithm have been used to select the feature gene. Diagnostic models were developed using SVM, RF, and Logistic Regression (LR). A ROC curve was used to evaluate the performance of the model. The compound-gene relationship was obtained from the Comparative Toxicogenomics Database (CTD). Results: The identification of three immune subtypes in SSc samples was based on the expression profiles of immune cells. The utilization of 19 key intersectional DEGs among subtypes facilitated the classification of SSc patients into three robust subtypes (gene_ClusterA-C). Gene_ClusterA exhibited significant enrichment of B cells, while gene_ClusterC showed significant enrichment of monocytes. Moderate activation of various immune cells was observed in gene_ClusterB. We identified 8 feature genes. The SVM model demonstrating superior diagnostic performance. Furthermore, correlation analysis revealed a robust association between the feature genes and immune cells. Eight pertinent compounds, namely methotrexate, resveratrol, paclitaxel, trichloroethylene, formaldehyde, silicon dioxide, benzene, and tetrachloroethylene, were identified from the CTD. Conclusion: The present study has effectively devised an innovative molecular subtyping methodology for patients with SSc and a diagnostic model based on machine learning to aid in clinical treatment. The study has identified potential molecular targets for therapy, thereby offering novel perspectives for the treatment and investigation of SSc.

Rapamycin Responds to Alzheimer's Disease: A Potential Translational Therapy.

Alzheimer's disease (AD) is a sporadic or familial neurodegenerative disease of insidious onset with progressive cognitive decline. Although numerous studies have been conducted or are underway on AD, there are still no effective drugs to reverse the pathological features and clinical manifestations of AD. Rapamycin is a macrolide antibiotic produced by Streptomyces hygroscopicus. As a classical mechanistic target of rapamycin (mTOR) inhibitor, rapamycin has been shown to be beneficial in a variety of AD mouse and cells models, both before the onset of disease symptoms and the early stage of disease. Although many basic studies have demonstrated the therapeutic effects of rapamycin in AD, many questions and controversies remain. This may be due to the variability of experimental models, different modes of administration, dose, timing, frequency, and the availability of drug-targeting vehicles. Rapamycin may delay the development of AD by reducing ß-amyloid (Aß) deposition, inhibiting tau protein hyperphosphorylation, maintaining brain function in APOE ε4 gene carriers, clearing chronic inflammation, and improving cognitive dysfunction. It is thus expected to be one of the candidates for the treatment of Alzheimer's disease.

B cell subsets-related biomarkers and molecular pathways for systemic lupus erythematosus by transcriptomics analyses.

BACKGROUND: Systemic lupus erythematosus (SLE), an autoimmune disease, is characterised by B-cell abnormalities and a loss of tolerance that can produce autoantibody. However, the imperative genes and molecular pathways involved in the change of B cell populations remain unclear. METHODS: The expression of B cell subsets between SLE and healthy controls (HCs) was detected based on micro-array transcriptome data. The Weighted Gene Co-Expression Network Analysis (WGCNA) further revealed the co-expression modules of naïve and memory B cells. Whereafter, we performed the functional enrichment analysis, Protein-protein interaction (PPI) networks construction and feature selection to screen hub genes. Ultimately, we recruited SLE patients and HCs from the Second Hospital of Shanxi Medical University and further verified these genes in transcriptome sequencing samples. RESULTS: Total of 1087 SLE patients and 86 HCs constituted in the study. Compared to HCs, the levels of peripheral naïve B cells of SLE patients decreased, while memory B cells increased. WGCNA identified two modules with the highest correlation for the subsequent analysis. The purple module was primarily in connection with naïve B cells, and the GO analysis indicated that these genes were mainly abundant in B cell activation. The blue module relevant to memory B cells was most significantly enriched in the "defence response to virus" correlation pathway. Then we screened six hub genes by PPI and feature selection. Finally, four biomarkers (IFI27, IFITM1, MX2, IRF7) were identified by transcriptome sequencing verification. CONCLUSION: Our study identified hub genes and key pathways associated with the naïve and memory B cells respectively, which may offer novel insights into the behaviours of B cells and the pathogenesis of SLE.

Genetic Evidence Supporting a Causal Association Between mTOR-Dependent EIF-4E Circulating Protein Level and Osteoporosis.

INTRODUCTION: The mechanistic target of rapamycin (mTOR) regulates bone homeostasis, a crucial factor in osteoporosis (OP) development. However, most research is based on observational studies, and the causality remains uncertain. Therefore, we analyzed two samples of mendelian randomization (MR) to determine whether there is a causal relationship between mTOR-dependent circulating proteins and OP. METHODS: Mendelian weighting (weighted median [WM], inverse variance weighting [IVW], and MR-Egger regression) were applied to analyze the causality between bone phenotypes (bone mineral density [BMD] in forearm, femoral neck, lumbar spine, and heel) and mTOR-dependent circulating proteins (RP-S6K, 4EBP, EIF-4E, EIF-4A, and EIF-4G). Horizontal pleiotropy and heterogeneities were detected using Cochran's Q test, MR-Pleiotropy RE-Sidual Sum and Outlier (MR-PRESSO), and "leave-one-out" analysis. The proteomics-GWAS INTERVAL study was used to select the instrumental variables (IVs) for mTOR proteins. RESULTS: As phenotypes for OP, estimations of BMD were taken in four different sites: forearm (FA) (n = 8143), femoral neck (FN) (n = 32,735), lumbar spine (LS) (n = 28,498), and heel (eBMD) (n = 426,824). Based on IVW analysis, EIF4E is causally related to FA-BMD (OR = 0.938, 95% CI 0.887, 0.991, p = 0.024) but not to BMD elsewhere. CONCLUSION: MR analysis revealed a causal relationship between EIF-4E and FA-BMD, which may provide new insights into the underlying pathogenesis of OP and a new therapeutic target for OP.

Identifying cellular senescence associated genes involved in the progression of end-stage renal disease as new biomarkers.

BACKGROUND: Cellular senescence plays an essential role in the development and progression of end-stage renal disease (ESRD). However, the detailed mechanisms phenomenon remains unclear. METHODS: The mRNA expression profiling dataset GSE37171 was taken from the Gene Expression Omnibus (GEO) database. The cell senescence-associated hub genes were selected by applying protein-protein interaction (PPI), followed by correlation analysis, gene interaction analysis, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. We next explored the relationships of hub genes with miRNAs, TFs, and diseases. The absolute abundance of eight immune cells and two stromal cells were calculated by MCPcount and the correlation of hub genes with these ten cells was analyzed. Lasso was used to selecting for trait genes. ROC curves and DCA decision curves were used to assess the accuracy and predictive power of the trait genes. RESULTS: A total of 65 cellular senescence signature genes were identified among patients and controls. The PPI network screened out ten hub genes. GO and KEGG indicated that ten hub genes were associated with ESRD progression. Transcription factor gene interactions and common regulatory networks of miRNAs were also identified in the datasets. The hub genes were significantly correlated with immune cells and stromal cells. Then the lasso model was constructed to screen out the five most relevant signature genes (FOS, FOXO3, SIRT1, TP53, SMARCA4). The area under the ROC curve (AUC) showed that these five characteristic genes have good resolving power for the diagnostic model. CONCLUSIONS: Our findings suggested that cellular senescence-associated genes played an important role in the development of ESRD and immune regulation.