Risk, Prognosis And Genetics Of Systemic Lupus Erythematosus-related Pulmonary Hypertension

Part ?:Predicting Risk of Pulmonary Arterial Hypertension in Systemic Lupus ErythematosusObjectivesPulmonary arterial hypertension is a life-threatening complication of systemic lupus erythematosus.However,there is no algorithm to identify those at high risk.We aimed to develop a prediction model for pulmonary arterial hypertension in lupus patients that provides individualized risk estimates.MethodsA multicenter,longitudinal cohort study was undertaken from January 2003 to January 2020.The study collected data on 3,624 consecutively evaluated patients diagnosed with lupus.The diagnosis of pulmonary arterial hypertension was confirmed by right heart catheterization.Cox proportional hazards regression and least absolute shrinkage and selection operator were used to fit the model.Model discrimination,calibration,and decision curve analysis were assessed for validation.ResultsNinety-two lupus patients developed pulmonary arterial hypertension(2.54%)at a median follow-up of 4.84 years(interquartile range,2.42-8.84).The final prediction model included five clinical variables(acute/subacute cutaneous lupus,arthritis,renal disorder,thrombocytopenia,and interstitial lung disease)and three autoantibodies(anti-RNP,anti-Ro/SSA and anti-La/SSB).A 10-year pulmonary arterial hypertension probability-predictive nomogram was established.The model was internally validated by C statistic(0.78),the Brier score(0.03),and a satisfactory calibration curve.According to the net benefit and predicted probability thresholds,we recommend annual screening in high-risk(>4.62%)lupus patients.ConclusionsWe developed a risk stratification model using routine clinical assessments.This new tool may effectively predict the future risk of pulmonary arterial hypertension in patients with systemic lupus erythematosus.Part ?:A Prognostic Model for Systemic Lupus Erythematosus-associated Pulmonary Arterial HypertensionObjectivesPulmonary arterial hypertension is a major cause of death in systemic lupus erythematosus,but there is no validated algorithm to identify patients who are at the highest risk.To develop a practical model for predicting long-term prognosis in patients with systemic lupus erythematosus-associated pulmonary arterial hypertension.MethodsA prognostic model was developed from a multicenter,longitudinal national cohort of consecutively evaluated patients with systemic lupus erythematosus-associated pulmonary arterial hypertension.The study was conducted between November 2006 and February 2020.All-cause death was defined as the endpoint.Cox regression and least absolute shrinkage and selection operators were used to fit the model.Internal validation of the model was assessed by discrimination and calibration using bootstrapping.ResultsOf 310 patients included in the study,81(26.1%)died within a median follow-up of 5.94 years(interquartile range 4.67-7.46).The final prognostic model included eight variables:modified World Health Organization functional class,6-minute walking distance,pulmonary vascular resistance,estimated glomerular filtration rate,thrombocytopenia,mild interstitial lung disease,N-terminal pro-brain natriuretic peptide/brain natriuretic peptide level,and direct bilirubin level.A 5-year death probability predictive algorithm was established and validated using the C-index(0.77)and a satisfactory calibration curve.Risk stratification was performed based on the predicted probability to improve clinical decision-making.ConclusionsThis new risk stratification model for systemic lupus erythematosus-associated pulmonary arterial hypertension may provide individualized prognostic probability using readily obtained clinical risk factors.External validation is required to demonstrate the accuracy of this model's predictions in diverse patient populations.Part ?:Whole Exome Sequencing in Systemic Lupus Erythematosus-associated Pulmonary Arterial HypertensionObjectivesGenetic predisposition is an important risk factor for systemic lupus erythematosus associated pulmonary arterial hypertension.However,the mutated genes in systemic lupus erythematosus associated pulmonary arterial hypertension have not yet to be explored.We aim to explore the mutated genes in systemic lupus erythematosus associated pulmonary arterial hypertension based on the whole-exome sequencing.MethodsPeripheral blood sample of disease group were obtained from patients with systemic lupus erythematosus associated pulmonary arterial hypertension in CSTAR-PAH cohort,while sample of control group were from health control in Huada Gene Technology Co.Ltd(Shenzhen,China).Peripheral blood samples were collected and genomic DNA was extracted using a DNA extraction kit.Exome library preparation and high-throughput sequencing were performed using an Illumina technology.We identified the common mutation and the rare mutation though bioinformatic analysis.ResultsThis study included 150 patients with systemic lupus erythematosus associated pulmonary arterial hypertension and 1000 health controls.Data quality was good in all samples.According to the single point Genetic association analysis,STK11?MROH5?PFKFB3 were identified as common mutations.Gene based burden analysis showed that DMTF1?ALMS1 and TRAF5 were rare mutations,and those were identified as deleterious mutations.Besides,more research are needed to explore the gene function and mechanism of TRAF5 in systemic lupus erythematosus associated pulmonary arterial hypertension.Conclusionswe explore the causative gene in systemic lupus erythematosus associated pulmonary arterial hypertension based on the CSTAR-PAH cohort.