| Objective:To explore primary Sj(?)gren's syndrome-associated pulmonary arterial hypertension(pSS-PAH)with its clinical characteristics,risk factors,rate of survival and achieving treatment goals,prognosis factors and biomarkers.This study aimed to provide clinical evidence to facilitate the early diagnosis,prognosis evaluation and strategy of goal-oriented therapy of pSS-PAH.Methods:We recruited the patients from Peking Union Medical Hospital(PUMCH)and eight other connective tissue disease associated pulmonary arterial hypertension clinical centers in China and established the single-center and multi-center cohort.Patients who fulfilled the classification criteria of pSS were enrolled.PAH was diagnosed by right heart catheterization(RHC)and their baseline and follow-up data were collected.In clinical study,cross-sectional analysis was conducted to describe the clinical characteristics.Case-control study between pSS-PAH and pSS-nonPAH patients was conducted to identify the risk factors of PAH using Logistic regression analysis.In prognostic study,the primary clinical end-point event was all cause mortality and the secondary end-point event was achieving PAH treatment goal.Cumulative probabilities of the end-points events were calculated by the Kaplan-Meier curve.Cox regression analysis was also conducted to identify the prognostic factors.In biomarker study,the association between genetic background and the development of PAH was investigated by determining Single Nucleotide Polymorphisms(SNPs)among pSS-PAH,pSS-nonPAH and health controls.Results:One hundred and five patients from multi-center were enrolled including 64 patients from PUMCH.In clinical study:(1)baseline characteristics:the majority of pSS-PAH patients were female(97.1%),and having the onset of PAH at the age of 41.1.PAH was the first manifestation among 46.7%patients.The activity and damage degree of pSS were low(ESSDAI:6;SSDDI:2).The mean pulmonary arterial pressure was 48.1 mmHg,and the cardiac index was 2.6L/(minxm2).The primary therapy was the combination of immunosuppressive agents and targeted drugs(68.6%).(2)risk factor:anti-SSB antibody(p<0.001,OR=4.095,95%CI[2.183,7.681])and anti-U1RNP antibody(p<0.001,OR=29.518,95%CI[6.026,144.600])were identified as the independent risk factors of pSS-PAH patients,while the the age of pSS onset(p<0.001,ORF=0.651,95%CI[0.524,0.810])and positivity of corneal staining(p=0.003,OR=0.409,95%CI[0.229,0.732])as the independent protective factors.(3)survival analysis:the 1,3,5-year survival rate were 94.0%,88.8%and 79.0%.Cardiac Index<2.5 L/(min×m2)(CI,p=0.044,HR=8.393,95%CI[1.060,66.475])and SSDDI(p=0.031,HR=1.446,95%CI[1.035,2.021])were identified as the independent survival predictors.(4)goal-achieving analysis:the 1,3,5-year rate of goal-achieving were 40.6%,67.4%and 73.9%.The anteroposterior diameter of right ventricle?32mm(p=0.017,HR=0.345,95%CI[0.44,0.829])and the use of immunosuppressant(p=0.032,HR=3.746,95%CI[1.124,12.490])were identified as independent predictors of goal achieving.Results of biomarker study:under dominant genetic model,there was significant difference of EBF1 rs3843489(p=0.042,ORF=2.367,95%CI[1.019,5.497])and STAT4 rs10168266(p=0.012,OR=0.378,95%CI[0.175,0.815])between pSS-PAH and pSS-nonPAH group.Conclusion:This study established the largest pSS-PAH multi-center cohort based on RHC diagnosis in the world.The regular screening of PAH in subclinical stage is recommended in pSS patients with risk factors such as early onset of pSS,anti-SSB and anti-UIRNP antibodies.The prognosis of pSS-PAH is poor,and the patients with poor cardiac function,right ventricle enlargement and involvement of multiple organs should receive intensive therapy which based on immunosuppressant.The biomarker study indicated EBF1 rs3843489 and STAT4 rs1016826 might be the novel biomarker of pSS-PAH.The genetic background of pSS-PAH might be more like that of pSS than Idiopathic PAH. |
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