Clinial Study And Biomarker Study Of Systemic Lupus Erythematosus-associated Pulmonary Arterial Hypertension

Objective:We started single-center and multi-center cohorts of systemic lupus erythematosus-associated pulmonary arterial hypertension (SLE-PAH) and investigated the baseline characteristics, risk factors, prognosis factors, therapeutic efficacy predictors and diagnostic/prognostic biomarkers of the disease. This study aims to provide clinical evidence for the early diagnosis, prognosis predicting and personalized treatment selection of SLE-PAH.Methods:This study involved Peking Union Medical Hospital (PUMCH) and thirteen CTD-PAH centers in China. Patients fulfilled the criteria of SLE and diagnosed by right heart catheterization (RHC) were enrolled in our study. Baseline and follow-up data were collected. In clinical study, cross sectional analysis was conducted to describe the baseline characteristics. Case-control study between patients with SLE-PAH and SLE-nonPAH was conducted to identify the risk factors. In prognostic study, the primary endpoint was all-cause mortality and the secondary endpoint was meeting PAH treatment goals. Cumulative probabilities of the endpoints were calculated using the Kaplan-Meier estimator. Cox regression was also conducted to identify the prognostic factors. Patients from PUMCH with baseline immunosuppressive therapy alone or in combination with PAH vasodilators were evaluated before and after the treatment and theraputic efficacy predictor was further investigated. In biomarker study, the serum level of anti-bone morphogenetic protein (BMP) receptor antibodies (including anti-BMPR2 antibody, anti-ALK1 antibody and anti-BMPRIA antibody) and growth differential factor-15 (GDF-15) were tested between healthy controls, SLE patients without PAH and patients with SLE-PAH. Further study of diagnostic/prognostic factors were also conducted regarding to the above proteins as well as endothelin type A/B receptor antibody (ERAb).Results:155 patients were enrolled in single center cohort and 310 patients were enrolled in multi-center study. Results of clinical study:1. Baseline characteristics. In single-center and multi-center cohort respectively, the percentages of female patients were 98% and 99%, and the age at recruitment were 34.2+8.4 and 34.8±9.9 years old. Early diagnostic rate by RHC were 36.6% and 41.6%. The mean pulmonary arterial pressure was 46.43±11.2mmHg and 46.4±12.0mmHg.100% and 99.4% of patients were treated with glucocorticoid.92.3% and 96.1% of patients were treated with immunosuppressive agents.62.7% and 69.4% of patients were treated with PAH vasodilators.2. Risk factors. Combined with interstitial lung disease, serositis, anti-U1RNP antibody, anti-SSA antibody and DLCO/Pred<70% were identified as independent risk factors for developing PAH in SLE patients.3. Survival analysis. The 1,3,5-year survival rates were 92.0-94.9%,84.7-85.6% and 73.0-73.9%. RAP≤5 mmHg was identified as independent survival predictors in single-center study. RAP≤10mmHg and CI≥2.5 L/min×m2 were identified as independent survival predictors in multi-center study.4. Reaching treatment goals analysis. The 1,3,5-year rates of patients reaching treatment goals were 31.6-44.8%,54.3-62.8%,63.2-68.9%. PAH early diagnosis by RHC, low complement and CI>2.5 L/min×m2 were identified as independent predictors of treatment goal reaching in single-center study. Serositis, CI>2.5 L/min×m2 and 6MWD>380 meters were identified as independent predictors of treatment goal reaching in multi-center study.5. Treatment efficacy analysis. Patients with first-line immunosuppressive therapy combined with PAH vasodilators were characterized by poor hemodynamic status. The defined responsor to treatment was a comprehensive indicator of the disease severity change and associated with the long term survival of patients. Patients with preserved cardiac function, short PAH disease duration and active SLE status may respond to the therapies. We observed disease severity was continually stable after PAH vasodilators ceased in seven patients meeting PAH treatment goals. Results of biomarker study:The rate of patients reaching PAH treatment goals in patients with positive ERAb was significantly higher than in those with negative ERAb group. Anti-BMPR1A antibody was significantly higher in SLE-PAH group than in other groups, but its relationship with prognosis was not identified. GDF-15 was significantly higher in SLE-PAH group than in other groups and GDF-15>1200pg/ml was identified as a predictor of poor survival.Conclusion:The world largest RHC-based SLE-PAH cohort was established in our study. Risk factors were identified and regular screening of PAH is recommended in SLE patient with risk factors for early detection. Prognostic factors were also identified and indicating that patients with prognostic factor of poor clinical outcome are recommended to evaluate the disease closely and start strengthened treatment earlier. Several new biomarkers were identified in our study with potential diagnostic and prognostic value in future clinical scenario.