Comparison of biologics and small-molecule drugs in axial spondyloarthritis: a systematic review and network meta-analysis.

Background: Biologics and small-molecule drugs have become increasingly accepted worldwide in the treatment of axial spondyloarthritis (axSpA), including ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA). However, a quantitative multiple comparison of their efficacy and safety is lacking. This study aims to provide an integrated assessment of the relative benefits and safety profiles of these drugs in axSpA treatment. Methods: We included randomized clinical trials that compared biologics and small-molecule drugs in the treatment of axSpA patients. The primary outcomes assessed were efficacy, including the Assessment of SpondyloArthritis International Society (ASAS) improvement of 20% (ASAS20) and 40% (ASAS40). Safety outcomes included treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). We used the surface under the cumulative ranking (SUCRA) curve value and ranking plot to evaluate and rank clinical outcomes and safety profiles of different treatments. The two-dimensional graphs were illustrated to visually assess both the efficacy (horizontal axis) and safety (vertical axis) of each intervention. Results: Our analysis included 57 randomized clinical trials involving a total of 11,787 axSpA patients. We found that seven drugs (TNFRFc, TNFmAb, IL17Ai, IL17A/Fi, IL17RAi, JAK1/3i, and JAK1i) were significantly more effective in achieving ASAS20 response compared to the placebo (PLA). Except for IL17RAi, these drugs were also associated with higher ASAS40 responses. TNFmAb demonstrated the highest clinical response efficacy among all the drugs. Subgroup analyses for AS and nr-axSpA patients yielded similar results. IL17A/Fi emerged as a promising choice, effectively balancing efficacy and safety, as indicated by its position in the upper right corner of the two-dimensional graphs. Conclusion: Our findings highlight TNFmAb as the most effective biologic across all evaluated efficacy outcomes in this network meta-analysis. Meanwhile, IL17A/Fi stands out for its lower risk and superior performance in achieving a balance between efficacy and safety in the treatment of axSpA patients.

Trace metal exposure and risk assessment of local dominant fish species in the Beijiang River Basin of China: A 60 years' follow-up study.

The Beijiang River, one of the Pearl River tributaries located in Guangdong, China, plays a critical role in providing water and fishery resources for the Pearl River Delta and receiving a large amount of domestic and industrial wastewater. However, due to the lack of historical monitoring data, we are unable to fully understand the relationship between the industrial and agricultural development and the environment. In this study, fish specimens collected from the Beijiang River Basin over a span of nearly 60 years (1963-2021) are used as research objects and the concentrations of ten trace metals (TMs) in two locally dominant fish species were determined by an inductively coupled plasma mass spectrometer. The human health risks caused by consuming fishes were assessed. Results show a correlation between the levels of TMs in fish muscle and the degree of industrialization. The concentrations of Cr, Mn, Ni, and Cu peaked during the period of 1981-1983, when China's industrial development was rapidly expanding while the environmental protection facilities were incomplete. However, with the implementation of Ecological Civilization policy, the levels of Cr, Mn, Ni, Cu, Cd, and Ba showed a downward trend in the period from 2018 to 2021. Cu concentrations in both fish muscle and viscera exhibit analogous change patterns across different periods, indicating that Cu serves as a significant indicator of TM pollution in the Beijiang River Basin. The presence of TMs in fish muscle often exhibits long-term enrichment, while those in the viscera demonstrate short-term accumulation. Based on the estimated daily intake, the target hazard quotient (THQ), and total THQ value, the overall health risk associated with TMs in fish from the Beijiang River Basin is low. However, certain TMs in the fish rebounded during 2018-2021, posing a potential risk for aquatic biology and ecosystems, which is worth our attention.

What adverse health effects will environmental heavy metal co-exposure bring us: based on a biological monitoring study of sanitation workers.

To investigate the relationship between health effect profile and co-exposure to heavy metal, 254 sanitation workers from Guangzhou, China, were recruited. Ten urinary metals were determined by inductively coupled plasma mass spectrometry. Parameters of physical examination, including blood lipid metabolism, renal function, blood pressure, and lung function, were tested for each participant. The hazard quotients (HQs) of eight heavy metals were evaluated. Cobalt, copper (Cu), molybdenum (Mo), nickel (Ni), and tin (Sn) demonstrated the top five associations with human health with the ∑19ß as 2.220, 1.351, 1.234, 0.957, and 0.930, respectively. Most physical examination parameters of workers were under the normal ranges, except the levels of forced mid expiratory flow rate (MMEF75/25), the maximum expiratory flow rate at 25% vital capacity (MEF25) and apolipoprotein B in the first quartile, and the level of uric acid in the third quartile of sanitation works. Moreover, Cu was significantly associated with diastolic pressure, pulse, and high density lipid (p < 0.05). Each unit increase in Mo level was related to a 120% increase odd ratio (OR) of abnormal of systolic pressure, but was significantly and negatively correlated with high density lipoprotein and apolipoprotein A, suggesting that Mo exposure may be a risk factor of cardiovascular disease. Each unit increase in Ni and Sn levels was associated with an increased OR of abnormal rate of MMEF75/25 and MEF25 (p < 0.001), suggesting the increasing risks of respiratory diseases. Sanitation workers exposed to Ni and Pb alone had no carcinogenic risks (HQ < 1). However, 23.8%, 34.6%, and 87.3% of sanitation workers confronted non-carcinogenic risks when exposed to Cu, Mo alone (HQ > 1), or co-exposed to the four heavy metals (HI > 1). Our study preliminarily revealed the potential sensitive health indicators of heavy metal co-exposure, which will provide beneficial health protection suggestions for the occupational populations.

IgG Immunocomplexes Drive the Differentiation of a Novel Subset of Osteoclasts Independent of RANKL and Inflammatory Cytokines.

Potentiation of receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis by IgG immunocomplexes (ICs) is generally considered an important pathway leading to cartilage and bone destruction in rheumatoid arthritis (RA). However, whether IgG ICs possess pro-osteoclastogenic potential independent of RANKL and inflammatory cytokines is unclear. Here we demonstrate that by fully cross-linking human FcγRIIa (hFcγRIIa) or co-ligating hFcγRIIa and TLR4, IgG ICs alone could drive the differentiation of human blood monocytes into nuclear factor of activated T cells cytoplasmic 1 (NFATc1-negative nonclassical osteoclasts (NOCs). Surprisingly, IgG ICs could also overrule RANKL-induced classical osteoclast (COC) differentiation in vitro. In mouse model of collagen-induced arthritis, hFcγRIIa-transgenic, but not nontransgenic control, mice suffered from cartilage/bone destruction accompanied by the presence of NFATc1- NOCs lining the eroded cartilage surface in affected joints. Our results not only identify a novel subset of IC-induced NOCs but also provide a possible explanation for the uncoupling of FcγR-mediated cartilage destruction from RANKL-related bone erosion in autoinflammatory arthritis. © 2021 American Society for Bone and Mineral Research (ASBMR)..

Disease-Specific Autoantibodies Induce Trained Immunity in RA Synovial Tissues and Its Gene Signature Correlates with the Response to Clinical Therapy.

Much evidence suggests that trained immunity is inappropriately activated in the synovial tissue in rheumatoid arthritis (RA), but the underlying mechanism remains unclear. Here, we describe how RA-specific autoantibody deposits can train human monocytes to exert the hyperactive inflammatory response, particularly via the exacerbated release of tumor necrosis factor α (TNFα). Comparative transcriptomic analysis by plate-bound human IgG (cIgG) or ß-glucan indicated that metabolic shift towards glycolysis is a crucial mechanism for trained immunity. Moreover, the cIgG-trained gene signatures were enriched in synovial tissues from patients with ACPA- (anticitrullinated protein antibody-) positive arthralgia and undifferentiated arthritis, and early RA and established RA bore a great resemblance to the myeloid pathotype, suggesting a historical priming event in vivo. Additionally, the expression of the cIgG-trained signatures is higher in the female, older, and ACPA-positive populations, with a predictive role in the clinical response to infliximab. We conclude that RA-specific autoantibodies can train monocytes in the inflamed lesion as early as the asymptomatic stage, which may not merely improve understanding of disease progression but may also suggest therapeutic and/or preventive strategies for autoimmune diseases.

Efficacy and safety of IL-17 inhibitors for the treatment of ankylosing spondylitis: a systematic review and meta-analysis.

OBJECTIVES: To systematically assess the efficacy and safety of IL-17 inhibitors in patients with active ankylosing spondylitis. METHODS: A systematic review of the literature was performed for randomized controlled trials (RCTs) concerning IL-17 inhibitors in patients with ankylosing spondylitis. Meta-analyses were used to determine the efficacy and safety of the IL-17 inhibitors in the treatment of these patients. The primary endpoint was predefined as the proportion of patients with at least 20% improvement in the Assessment of Spondyloarthritis International Society (ASAS20) response criteria at week 16, and the secondary endpoint was defined as ASAS40 at week 16. RESULTS: Six phase III randomized, double-blind, placebo-controlled trials including 1733 patients (1153 patients received IL-17 inhibitors, including secukinumab or ixekizumab, whereas 580 patients received a placebo as comparators) were included. At week 16, the IL-17 inhibitor regimen produced a significant increase in the ASAS20 response rate (RR = 1.63, 95% CI 1.45 to 1.84, p = 0.00) and the secondary endpoint ASAS40 response rate (RR = 2.12, 95% CI 1.75 to 2.56, p = 0.00) versus those for the placebo. With respect to the safety profile, more treatment-emergent adverse events (RR = 1.11, 95% CI 1.01 to 1.22, p = 0.03) and non-severe infections (RR = 1.82, 95% CI 1.40 to 2.37, p < 0.001) were described after treatment with IL-17 inhibitors than after treatment with placebo, while no increased risk of other adverse events was indicated after IL-17 inhibitor therapy, including death, discontinuation due to adverse events, or serious adverse events. CONCLUSIONS: IL-17 inhibitors produced favorable response rates but an increased risk of non-severe infections in the treatment of active ankylosing spondylitis.

Identification of PBMC-expressed miRNAs for rheumatoid arthritis.

Post-transcriptional regulation by miRNAs plays an important role in the pathogenesis of rheumatoid arthritis (RA), however, the roles of specific miRNAs in RA pathogenesis remain largely unclear. This study performed dual-omics (miRNA and mRNA) integration analysis and in-depth cellular and molecular functional exploration to identify novel RA-associated miRNAs and to understand their underlying pathogenic mechanism. Based on the miRNA and mRNA expression profiles in peripheral blood mononuclear cells (PBMCs) from a discovery sample set (25 RA cases and 18 healthy controls), 18 differentially expressed miRNAs (DEMIRs) (|Fold-change|>2 and P < 0.05) were identified and corresponding interaction networks of DEMIRs and mRNA were constructed. After the expression validation of the DEMIRs in a validation sample set (35 RA cases and 35 healthy controls), miR-99b-5p was highlighted. The over-expression of newly discovered miR-99b-5p is able to suppress T cell apoptosis, promote cell proliferation and activation, increase expression of proinflammatory cytokines (IL-2, IL-6, TNF-α, and IFN-γ), and inhibit expression of its target genes mTOR and RASSF4. This study comprehensively identified PBMC-expressed miRNAs along with corresponding regulatory networks significant for RA and discovered miR-99b-5p as a novel post-transcriptional mediator involved in RA pathogenesis. The findings improved our understanding of RA pathogenesis and provided novel insights into the molecular mechanisms underlying RA pathogenesis.

Rheumatoid arthritis-associated DNA methylation sites in peripheral blood mononuclear cells.

OBJECTIVES: To identify novel DNA methylation sites significant for rheumatoid arthritis (RA) and comprehensively understand their underlying pathological mechanism. METHODS: We performed (1) genome-wide DNA methylation and mRNA expression profiling in peripheral blood mononuclear cells from RA patients and health controls; (2) correlation analysis and causal inference tests for DNA methylation and mRNA expression data; (3) differential methylation genes regulatory network construction; (4) validation tests of 10 differential methylation positions (DMPs) of interest and corresponding gene expressions; (5) correlation between PARP9 methylation and its mRNA expression level in Jurkat cells and T cells from patients with RA; (6) testing the pathological functions of PARP9 in Jurkat cells. RESULTS: A total of 1046 DNA methylation positions were associated with RA. The identified DMPs have regulatory effects on mRNA expressions. Causal inference tests identified six DNA methylation-mRNA-RA regulatory chains (eg, cg00959259-PARP9-RA). The identified DMPs and genes formed an interferon-inducible gene interaction network (eg, MX1, IFI44L, DTX3L and PARP9). Key DMPs and corresponding genes were validated their differences in additional samples. Methylation of PARP9 was correlated with mRNA level in Jurkat cells and T lymphocytes isolated from patients with RA. The PARP9 gene exerted significant effects on Jurkat cells (eg, cell cycle, cell proliferation, cell activation and expression of inflammatory factor IL-2). CONCLUSIONS: This multistage study identified an interferon-inducible gene interaction network associated with RA and highlighted the importance of PARP9 gene in RA pathogenesis. The results enhanced our understanding of the important role of DNA methylation in pathology of RA.

IgG Immunocomplexes Sensitize Human Monocytes for Inflammatory Hyperactivity via Transcriptomic and Epigenetic Reprogramming in Rheumatoid Arthritis.

Prevalence of circulating immunocomplexes (ICs) strongly correlates with rheumatoid arthritis (RA) in humans. Deposits of IgG-ICs are abundant in affected joints of patients, yet molecular mechanisms for the pathogenic roles of such ICs are not fully understood. In this study, we present evidence that IgG-ICs precipitated from RA sera sensitized human monocytes for a long-lasting inflammatory functional state, characterized by a strong TNF-α response to cellular proteins representing damage-associated molecular patterns and microbe-derived pathogen-associated molecular patterns. Importantly, plate-coated human IgG (a mimic of deposited IC without Ag restriction) exhibited a similarly robust ability of monocyte sensitization in vitro. The plate-coated human IgG-induced functional programming is accompanied by transcriptomic and epigenetic modification of various inflammatory cytokines and negative regulator genes. Moreover, macrophages freshly isolated from synovia of patients with RA, but not sera-negative arthropathy, displayed a signature gene expression profile highly similar to that of IC-sensitized human monocytes, indicative of historical priming events by IgG-ICs in vivo. Thus, the ability of IgG-ICs to drive sustainable functional sensitization/reprogramming of monocytes and macrophages toward inflammation may render them key players in the development of RA.

Identification of expression quantitative trait loci (eQTLs) in human peripheral blood mononuclear cells (PBMCs) and shared with liver and brain.

PBMCs are essential for immunity and involved in various diseases. To identify genetic variations contributing to PBMCs transcriptome-wide gene expression, we performed a genome-wide eQTL analysis by using genome-wide SNPs data and transcriptome-wide mRNA expression data. To assess whether there are common regulation patterns shared among different tissues/organs, public datasets were utilized to identify common eQTLs shared with PBMCs in lymphoblastoid, monocytes, liver, and brain. Allelic expression imbalance (AEI) assay was employed to validate representative eQTLs identified. We identified 443 cis- and 2386 trans-eSNPs (FDR <0.05), which regulated 128 and 635 target genes, respectively. A transcriptome-wide expression regulation network was constructed, highlighting the importance of 28 pleiotropic eSNPs and 18 dually (cis- and trans-) regulated genes. Three genes, that is, TIPRL, HSPB8, and EGLN3, were commonly regulated by hundreds of eSNPs and constituted a very complex interaction network. Strikingly, the missense SNP rs371513 trans- regulated 25 target genes, which were functionally related to poly(A) RNA binding. Among 8904 eQTLs (P < 0.001) identified herein in PBMCs, a minority (163) was overlapped with lymphoblastoid, monocytes, liver, and/or brain. Besides, two cis-eSNPs in PBMC were confirmed by AEI. The present results demonstrated a comprehensive expression regulation network for human PBMCs and may provide novel insights into the pathogenesis of immunological diseases related to PBMCs.

Multiple correlation analyses revealed complex relationship between DNA methylation and mRNA expression in human peripheral blood mononuclear cells.

DNA methylation is an important regulator on the mRNA expression. However, a genome-wide correlation pattern between DNA methylation and mRNA expression in human peripheral blood mononuclear cells (PBMCs) is largely unknown. The comprehensive relationship between mRNA and DNA methylation was explored by using four types of correlation analyses and a genome-wide methylation-mRNA expression quantitative trait locus (eQTL) analysis in PBMCs in 46 unrelated female subjects. An enrichment analysis was performed to detect biological function for the detected genes. Single pair correlation coefficient (r T1) between methylation level and mRNA is moderate (-0.63-0.62) in intensity, and the negative and positive correlations are nearly equal in quantity. Correlation analysis on each gene (T4) found 60.1% genes showed correlations between mRNA and gene-based methylation at P < 0.05 and more than 5.96% genes presented very strong correlation (R T4 > 0.8). Methylation sites have regulation effects on mRNA expression in eQTL analysis, with more often observations in region of transcription start site (TSS). The genes under significant methylation regulation both in correlation analysis and eQTL analysis tend to cluster to the categories (e.g., transcription, translation, regulation of transcription) that are essential for maintaining the basic life activities of cells. Our findings indicated that DNA methylation has predictive regulation effect on mRNA with a very complex pattern in PBMCs. The results increased our understanding on correlation of methylation and mRNA and also provided useful clues for future epigenetic studies in exploring biological and disease-related regulatory mechanisms in PBMC.

Integrative multi-omics analysis revealed SNP-lncRNA-mRNA (SLM) networks in human peripheral blood mononuclear cells.

Long non-coding RNAs (lncRNAs) serve as important controller of cellular functions via regulating RNA transcription, degradation and translation. However, what are the regulation patterns of lncRNAs on downstream mRNA and how the upstream genetic variants regulate lncRNAs are largely unknown. We first performed a comprehensive expression quantitative trait locus (eQTL) analysis (MatrixeQTL package, R) using genome-wide lncRNA expression and SNP genotype data from human peripheral blood mononuclear cells (PBMCs) of 43 unrelated individuals. Subsequently, multi-omics integrative network analysis was applied to construct SNP-lncRNA-mRNA (SLM) interaction networks. The causal inference test (CIT) was used to identify lncRNA-mediated (epi-) genetic regulation on mRNA expressions. Our eQTL analysis detected 707 pairs of cis-effect associations (p < 5.64E-06) and 6657 trans-effect associations (p < 3.51E-08), respectively. We also found that top significant cis-eSNPs were enriched around the lncRNA transcription start site regions, and that enrichment patterns of cis-eSNPs differs among different lncRNA sizes (small, medium and large).The constructed SLM interaction networks (1 primary networks and four small separate networks) showed various complex interaction patterns. Especially, the in-depth CIT detected 50 significant lncRNA-mediated SLM trios, and some hotspots (e.g., SNPs: rs926370, rs7716167 and rs16880521; lncRNAs: HIT000061975 and ENST00000579057.1). This study represents the first effort of dissecting the SLM interaction patterns in PBMCs by multi-omics integrative network analysis and causal inference test for clearing the regulation chain. The results provide novel insights into the regulation patterns of lncRNA, and may facilitate investigations of PBMC-related immune physiological process and immunological diseases in the future.

[Study on regulatory effect of Bushen Antai Recipe on levels of estrogen and progesterone in blastocyst implantation dysfunction mice].

OBJECTIVE: To investigate the effect and explore the mechanism of Bushen Antai Recipe (BAR) on pregnancy rate and number of implantation site in blastocyst implantation dysfunction (BID) mice induced by indomethacin. METHODS: Pregnant mice were divided into 3 groups randomly: the normal group, the model group and the BAR group. Tap water was given orally to the rats in the normal and model groups, and BAR to the rats in the BAR group from the first day of pregnancy for 5 or 8 days; on the 3rd and 4th day dissolvent was injected subcutaneously twice per day in the normal group, while indomethacin (4.33 mg/kg) was injected subcutaneously twice per day in the other two groups to establish implantation dysfunction model; serum estrogen (E) and progesterone (P4) levels were detected on the 5th and 8th day; the pregnancy rate and number of implanted site was observed and the receptors of E and P4 in endometrium of uterus were examined by immunohistochemistry on the 8th day. RESULTS: The pregnancy rate and number of implanted site was 27.3% and 5.3 +/- 0.7 respectively in the model group, significantly lower than those in the normal group (90.9%, 13.3 +/- 2.8), and the BAR group (72.7%, 10.7 +/- 2.2, P < 0.05). Serum E level was higher in the BAR group than that in the model group on the 5th and 8th day, and even higher than that in the normal group on the 8th day; serum P4 level was lower in the model and BAR groups than that in the normal group on the 5th day (P < 0.01), but higher in the BAR group than that in the model group on the 8th day. Immunohistochemical observation showed that expressions of E and P4 receptor increased remarkably in the BAR group than those in the model group. CONCLUSION: BAR increases the pregnancy rate and number of implanted site of indomethacrne induced BID mice through regulating E and P4 levels and enhancing the expressions of their receptors in the endometrium.

Effects of triptolide on the expression and activity of NF-kappaB in synovium of collagen-induced arthritis rats.

The expression and activity of NF-kappaB in the synovium of collagen-induced arthritis (CIA) rats was detected in order to investigate the possible therapeutic effects of triptolide on rheumatoid arthritis (RA). The experimental Wistar rat model of CIA was set up by intradermal injection of emulsion of bovine collagen II and the successful rate of setting-up models was evaluated by arthritis index (AI). Rats were grouped randomly into three groups: normal, model and treatment group. The expression of TNF-alpha and IL-6 in synovial fluid was detected by ELISA, and the expression and activity of NF-kappaB in synovium by immunohistochemistry method and by electrophoretic mobility shift assay (EMSA) respectively. As compared with normal group, the expression of TNF-alpha and IL-6 in synovia (P < 0.05), and the expression and activity of NF-kappaB (P < 0.05) in synovium were increased in model group. There was statistical difference in above-mentioned indexes between model group and treatment group. Triptolide may play a protective role in RA via downregulating the expression and activity of NF-kappaB in synovium.