Risk Factors Analysis Of Osteonecrosis In Systemic Lupus Erythematosus And Core Genes And Pathways In Lupus Related Cardiovascular Disease

Objective:Systemic lupus erythematosus(SLE)is a serious autoimmune disease that can cause inflammatory infiltration and cause permanent organ damage.Osteonecrosis(ON)characterized by the increased apoptosis and necrosis of osteocytes is a common complication of SLE,which could lead to limb pain,movement disturbance and ultimately disability.At present,the pathogenesis of SLE with osteonecrosis remains unclear.The purpose of this study was to explore the incidence and related risk factors of osteonecrosis in SLE,based on the Chinese population cohort.Methods:1158 patients with SLE had been consecutively recruited from Peking Union Medical College Hospital since 2009.All patients met the 1997 American Society of Rheumatology classification criteria for SLE.Patients who diagnosed with ON before SLE onset and lacking baseline data before enrolled in the group had been excluded.The demographic characteristics,clinical manifestations,and laboratory indexes were analyzed by univariate regression analysis,multivariate regression analysis and cox proportional hazard model between SLE patients with ON and those without ON.Results:Of all enrolled SLE patients enrolled,88 developed ON.The prevalence of ON in SLE patients is 7.6%.Among these 88 patients,57.1%reported isolated necrosis of the femoral head and 42.9%reported multiple joint involvement.The mean age of ON onset was 24.62±8.89 years,which was significantly lower than that in SLE patients without ON(27.23±10.16 years old).The disease duration of ON group was significantly longer than that in the control group(10.68±5.97,7.25 ± 5.60 years,respectively,p<0.001).The percentage of arthritis,kidney and central nervous system damage in ON group was 65.9%(p<0.05),57.6%(p<0.05)and 16.5%(p<0.05),respectively.At the same time,patients with osteonecrosis are more likely to take glucocorticoid(GC)therapy and high-dose GC in the early stage of SLE.The proportion of hydroxychloroquine in the non-ON group was significantly higher than that in the ON group(p<0.001).Cox regression analysis showed that central nervous system involvement and glucocorticoid therapy were two independent risk factors for osteonecrosis in patients with SLE.Antiphospholipid antibody is a risk factor for multiple osteonecrosis(OR:6.28,p=0.009).Conclusions:ON remains a serious and irreversible complication in SLE.In addition to glucocorticoid therapy,we found that central nervous system involvement is a risk factor for ON,while the administration of HCQ is a protective factor.The clinical characteristics of multiple sites ON patients are distinct from isolated femoral head necrosis patients.The positive aPLs are the risk factor for multiple site osteonecrosis.Objective:To analysis the differential genes(DEGs)and pathways in systemic lupus erythematosus(SLE)and antiphospholipid antibody syndrome(APS).Exploring the relationship between DEGs and cardiovascular-related events.Providing more evidence for potential treatment targets based on the disease molecular typing.Methods:The high-through chip data of SLE and APS patients were searched in Gene Expression Omnibus(GEO)database.The original dataset GSE50395 was downloaded from GEO and were further normalized and standardized by RStudio.The DEGs between disease groups and control group were visualized by packages of RStudio.We performed the gene ontology(GO)function and pathway enrichment analyses(Kyoto Encyclopedia of Genes and Genomes,KEGG)of DEGs in DAVID online analysis tool to interact the relationship between gene and biological function.Then we put the data into STRING database and constructed the DEGs protein-protein interaction network(PPI).Cytoscape software was used to visualize the analysis results,and the top ten genes obtained by 12 algorithms were intersected to determine the core genes.Gene set enrichment analysis(GSEA)software was used to analyze the signal pathways and biological functions related to core genes.Results:The monocytes transcriptome mcroarray data of these three groups were constructed by GO,KEGG,PPI and GSEA enrichment analysis.The molecular functions of DEGs in APS patients were mainly concentrated in G protein coupled receptor activity,receptor binding function,receptor regulatory activity and extracellular domain of cellular components.The biological functions were mainly involved in transmembrane transport and proteolysis.The main signal pathways were PI3K-AKT,MAPK and IL-7 pathway.The core genes for APS were FGF2 and MMP9.The biological processes of DEGs in SLE patients were focused on protein glycosylation,glycoprotein metabolism and glycoprotein biosynthetic process.Also,the cellular components were mainly focused on the cytoskeleton and extracellular region.The signal pathways were enriched in interferon-related pathway,JAK-STAT pathway,T cell signal receptor pathway and natural killer cell-mediated cytotoxicity.The core genes of SLE were STAT1 and DDX58.These screened genes were associated with cardiovascular disease and thrombosis.The molecular functions and biological process of DEGs in patients with APS plus SLE were familiar with the other two disease groups.The core genes screened from patients with APS plus SLE overlap with those from patients with SLE and APS,respectively.Conclusion:Through bioinformatics analysis,we identified specific genes to explain pro-atherosclerotic,pro-thrombotic and inflammatory process in the highly related autoimmune diseases.In APS patients,FGF2 and MMP9 in monocytes were the two core genes and related with the atherosclerosis and thrombosis development.PI3K-AKT and MAPK signal pathways were up-regulated in these patients,which also participated in the process of vascular endothelial cell injury and atherosclerosis development.STA T1 and DDX58 genes were the two core genes in monocytes of patients with SLE related to cardiovascular disease.Interferon synthesis related pathway and JAK-STAT pathway were the pathogenic process of endothelial cell injury and by production of proinflammatory cytokines.According to our analysis,the monocytes in the three disease groups presented common genetic characteristics.These characteristics indicated that monocytes play a central role in the development of atherosclerosis and cardiovascular disease.The monocytes alter their phenotype and biological functions under the stimulation of different cytokines and chemokines.Although the interaction among genetic factors,immune environment and treatment methods can determine the complicated clinical manifestations in autoimmune disease.Finding differentially expressed genes and pathways enable us to explore more precise therapeutic target in these chronic autoimmune diseases.