Clinical Features And Prognostic Analysis Of Takayasu Arteritis In Children And A Study Of Gut Microbiota In Patients With Takayasu Arteritis Based On Metagenomic And Metabolomic And Lipidomic Analysis

Part ?:Clinical course and prognostic factors of childhood Takayasu's arteritisBackground:Childhood Takayasu's arteritis(c-TA)is scarcely reported but characterized by devastating morbidity and mortality.This study aims to:1)investigate the clinical course of c-TA and prognostic factors associated with rehospitalization and events including vascular complications,flares,and death;2)investigate the clinical features and outcomes of c-TA hospitalized with hypertension;3)present the largest real-world scenario for c-TA patients undergoing interventions and their post-interventional outcomes.Methods:This study consecutively recruited inpatient c-TA cases(2002-2017)of Fuwai Hospital,Chinese Academy of Medical Sciences.Data on clinical,and therapeutic features were collected.Event-free survival,rehospitalization-free survival,post-interventional complication survival,re-intervention-free survival were projected by Kaplan-Meier methods.Associated factors for intervention and blood pressure control were assessed via Logistic regression models.Predictors for TA-related events,rehospitalization,post-interventional complications,re-interventions were assessed by COX regression models.Results:Firstly,101 patients(female,76.2%)were recruited with age of 14(interquartile range(IQR),12-16)years at c-TA onset.Hypertension(70.3%),blood pressure discrepancy(55.4%),bruits(51.5%)were core presentations with renal artery(62.4%),abdominal aorta(42.6%),subclavian artery(43.6%),and carotid artery(42.6%)mainly affected.Core administered treatment include glucocorticoids(78.2%),antiplatelet agents(72.3%),and revascularization(57.4%).At a median 2.4(IQR 0.7-6.1)years of follow-up,events and rehospitalization were observed in 44.6%and 37.6%,respectively.The three-year event-free survival and rehospitalization-free survival were 55%(95%CI,44.3%-67.3%)and 60.2%(95%CI,49.9%-72.5%).Body mass index(BMI)level(hazard ratio(HR)=0.49,95%confidence interval(CI)0.30-0.81,p=0.005),stroke(HR=7.37,95%CI 2.35-23.1,p=0.001),and revascularization(HR=0.51,95%CI 0.27-0.94,p=0.032)were predictors of events.Predictors(p<0.05)for rehospitalization include age at admission(HR=0.81),renal artery involvement(HR=0.49),and elevated C-reactive protein(CRP;HR=2.50).Secondly,the hypertensive cohort(n=71,28.2%males)as compared with non-hypertensive cohort had significantly fewer active diseases;fewer episodes of claudication,syncope,blurred vision,and myocardial ischemia;and fewer systemic symptoms(p<0.05).The hypertensive group presented with more localized type ? disease(50.7%vs.6.7%,p=0.001).Renovascular disease(78.9%vs.23,3%,p=0.001)were associated with hypertension.At the median 3-year follow-up,53%patients achieved BP control and 39%experienced TA-related events.The three-year event-free survival were 63.0%(95%CI 48.1%-74.7%),higher than in non-hypertensive group(p=0.014).Intervention(OR(odds ratio)=3.46)and baseline systolic BP(OR=0.96)were independent factors for BP control(p<0.05).Finally,69 patients underwent 121 interventions during 3.1-year follow-up.Technical success rate was 96.7%.Intervention was associated with male sex(OR=0.27,p=0.035)and type ? disease(OR=17,92,p=0.001).Male sex also marginally indicated risk for re-intervention(HR=3.22,p=0.05).Hypertension secondary to renal artery stenosis(RAS,59.4%)or mid-aorta stenosis(MAS,14.5%),heart failure(21.7%),claudication(21.7%)were leading clinical hints for interventions.Over 2.88 years since intervention,36 lesions occurred complications in 28 patients and 22 lesions need re-interventions in 17 patients,majorly on renal artery or mid-aorta.The three-year complication-free and re-intervention-free survivals were 59.5%(95%CI,44.9%-71.5%)and 75.4%(95%CI,60.5%-85.3%).Peri-interventional predictors of complications(p<0.05)include dual antiplatelet therapy(HR=031),concurrent surgery(HR=26.5),technical failure(HR=3.65).Male sex(HR=2.52),retinopathy secondary to hypertension(HR=3.41),pulmonary artery hypertension(PAH,HR=3.64)were baseline indicators(p<0.05).Conclusions:This large study of c-TA reveals an early 3%mortality at the first year since discharge and around 45%morbidity within three years.Hypertension,renal artery involvement,and revascularization with antiinflammation and antiplatelet medications dominate c-TA with indications for optimistic prognosis.Lower BMI level,younger age at admission,stroke,and elevated CRP indicates poor outcomes.Majority of patients have hypertension,more quiescent without typical systemic or ischemia symptoms,more localized abdominal lesions,higher proportion of revascularizations and better event-free survival.Three-year BP control is over 50%with intervention beneficial for BP control.Over two-thirds c-TA patients require interventions and three-year complication-free survival is 59.5%.Male sex,retinopathy,and PAH at baseline alert unfavorable outcomes.Interventions on MAS or RAS in c-TA need specific concerns.Peri-interventional dual antiplatelet therapy appears to protect c-TA from post-interventional complications.Part ?:Alterations of gut microbiome,metabolome and lipidome in Takayasu arteritisObjective:Mounting evidences have linked microbiome and metabolome to systemic autoimmunity and cardiovascular diseases.A rare disease sharing features of above diseases,Takayasu arteritis(TA),has limited information.This study aimed to characterize discriminatory gut dysbiosis,host metabolite and lipid profiles,and their crosstalk with disease phenotypes in TA.Methods:To address the discriminatory signatures,we performed shotgun sequencing of fecal metagenome across discovery(n=97,Fuwai Hospital,Chinese Academy of Medical Sciences)and validation(n=24,Shanxi Provincial People's Hospital)cohorts encompassing TA patients and healthy controls.Interrogation of untargeted metabolomics and lipidomics profiling of plasma and fecal samples was also employed to refine features mediating associations between microorganisms and TA phenotypes including inflammation indicators such as clinical disease activity evaluation scores,systemic inflammation biomarkers and vascular inflammation indicators,vascular involvement based on Hata and Numano's angiographic classification,medication prescription at discharge,prognostic indicators and follow-up outcome comprise of all-cause death,vascular complications,and disease relapse.Results:Firstly,a clear separation presented between TA and controls through non-metric multi-dimensional scaling based on Bray-Curtis distance,revealing altered beta-diversity(Adonis analysis,p=0.016).IL-2R and disease course were identified as significant contributing factors(p<0.01)correlating with microbial structures via envfit function.To control for the confounding potentials of disease course,age,sex,BMI,baseline steroid dose,and use of immunosuppressants,the taxonomical profiles associated with TA were then analyzed using a multivariate analysis(MaAsLin2)with eight differential genera and 16 differential species identified.Secondly,A total of 34 pathways were identified different in TA mainly involving in the biosynthesis of cofactor,carrier and vitamin,nucleoside and nucleotide,cell wall structure,phospholipid,sulfur compound metabolism,as well degradation of 4-aminobutanoate(GABA).Thirdly,by using the differential abundance analysis,clustering,clinical phenotype-filtering,and random forest(RF)disease classifying analysis,metabolomic,and lipidomic signatures were respectively identified with accurate performance on distinguishing TA,mainly involving in glycerophospholipid metabolism,alanine,aspartate and glutamate metabolism,porphyrin and chlorophyll metabolism,nicotinate and nicotinamide metabolism,arginine biosynthesis,sphingolipid metabolism,purine and pyrimidine metabolism.Then,microbiome derived signatures were directly or indirectly via metabolism correlated with TA clinical phenotypes of angiographic vascular involvement,systemic and vascular inflammation,discharge medication,and prognosis.Finally among them,a combination of ten bacterial species encompassing unclassified Escherichia,Veillonella parvula,Streptococcus parasanguinis,Dorea formicigenerans,Bifidobacterium adolescentis,Lachnospiraceae bacterium 7 158FAA,Escherichia coli,Streptococcus salivarius,Klebsiella pneumoniae,and Lachnospiraceae Bacterium 5 1 63FAA,could discriminate TA from controls with area under curves(AUCs)of 82.1%,98.0%and 94.8%in training,testing and independent validation sets,respectively.Conclusions:This study firstly identifies the discriminatory gut microbiome-derived signatures in TA.Dysbiosic microbial species also link to inflammation,injured vascular beds,treatment,outcome of TA directly or indirectly via metabolic and lipid modules.Further explorations on the microbiome-metagenome interface in TA subtype prediction and pathogenesis are thus indicated.