Establishment Of Clinical Cohort And Biomarker Of Antiphospholipid Syndrome

Background:Antiphospholipid syndrome (APS) is one of autoimmune diseases, clinically manifested by thrombosis (arterial or venous), pregnancy complications (recurrent pregnancy loss, pre-eclampsia, or placental insufficiency) and thrombocytopenia, with medium/high titers of anti-phospholipid antibodies(aPL). Up till now, there is still no valid treatment strategy based on etiology. There is no acknowledged standardized thrombosis risk stratification system, either. Multiple target organ impairments by repeated thrombosis events is still an urgent problem to be solved. In addition, previous studies of APS patients in China were all cross sectional studies, prospective or retrospective cohort studies haven’t been established yet, and knowledge about prognosis of APS was rare.Objectives:This study aim to establish a retrospective cohort of APS patients from Peking Union Medical College Hospital (PUMCH) in the past 10 years and investigate risk factors of thrombosis recurrence of APS patients based on data from cross sectional study. To establish prospective cohort of APS patients, we investigate diagnosis efficacy and clinical significance of aPL profiles.Methods:Clinical characteristics of APS patients were collected based on the case records from PUMCH inpatient department since 2005 or PUMCH outpatient department since November 2015. For the study population, collected clinical information at first diagnosis are as following:demographic characteristics, past medical history, personal history, family history, disease course, disease evaluation, laboratory test results, treatment strategy, etc. We set the time of discharge as baseline, collect blood sample, follow up the APS patients through telephone, clarify the prognosis and analyze outcome including death and thrombosis recurrence.Results:1.159 patients were included in the retrospective cohort study, among which 125 patients had no thrombosis recurrences,25 had thrombosis recurrences and 16 have passed away. Age at first diagnosis was 36.5±14.9, and number of male patients was 50.76 secondary APS patients were included, consisted of 73 SLE,2 RA,1 pSS. Among the 118 patients (74.2%) with thrombosis events in the past,74 had venous thrombosis,66 had arterial thrombosis, and 22 had both.92 patients showed antibodies targeting cardiolipin (aCL) positivity (57.9%),81 showed antibodies targeting beta2 glycoprotein I (anti-β2GPI) positivity (50.9%) and 116 showed lupus anticoagulant (LA) positivity (73.0%) with 93 double positivity3(58.5%) and 47 triple positivity 4 (29.6%).70 patients (44.0%) had thrombocytopenia (PLT<100×109/L),96(60.4%)had positive ANA test results,58(36.5%) had low level of C3(<0.73g/L),50(31.5%) had low level of C4(<0.1g/L),26(16.4%) had elevated level of IgG(>17g/L),80(50.3%) had faster ESR(>20mm/h), and 60(43.4%) had higher hsCRP(>3mg/L).114 patients(71.7%) were treated by anticoagulants,84(52.8%) by hydroxychloroquine, and 115(72.3%) by steroid. OR value of male patients was 1.964(p=0.051). When outcome event was all-cause mortality of APS patients, death causes of 16 patients were:8 thrombosis recurrences,3 infections,1 interstitial lung disease,1 renal failure, and 3 unknown causes. Besides,1-year survival rate of the patients was 92.5%, with 3-year survival rate 90.6% and 5-year survival rate 89.9%. When outcome event was all-cause unsteady state(death or thrombosis recurrence), 1-year stable rate (nonevent ratio)was 86.3%,3-year stable rate 82.5% and 5-year stable rate 81.9%. When outcome event was unsteady state attributed to thrombosis recurrence (including subsequent death),1-year stable rate (ratio of no thrombosis recurrence) was 91.2%,3-year stable rate 87.4% and 5-year stable rate 84.9%. In thrombotic APS patients,31.0% was secondary type(SAPS), and male dominated 90.9% of the primary one(PAPS). For patients with previous venous thrombosis, the ratio between PAPS and SAPS was1.7:1, and it turned to be 1.9:1 for those with previous arterial thrombosis. 14.3% PAPS patients showed triple positivity of the antibody profile, while 34.5% of SAPS patients showed triple positivity. Furthermore, more prevalence of ANA positivity, decreased C3 level, increased C4 and IgG level and hypertension was showed in SAPS patients.2.67 patients were included in the prospective cohort study. In the correlation study of antibody profile and arterial thrombosis events in APS patients, aCL-IgG positivity(OR=5.053, p=0.135), clinical aCL positivity(OR=3.070, p=0.305) and anti-β2GP1-IgG positivity(OR=1.005, p=0.056) were found to be the potential risk factor of arterial thrombosis. This was similar to the result of ROC curve analysis:aCL-IgG positivity(AUC=0.682, p=0.042), clinical aCL positivity(AUC=0.687, p=0.037) and anti-β2GP1-IgG positivity(AUC=0.660, p=0.074). Strong correlations were showed between total aCL and aCL-IgM(p=0.816, p=0.000), anti-β2GPI-IgM and aCL-IgM(p=0.953, p=0.000), anti-β2GPI-IgG and aCL-IgG(p=0.968, p=0.000) respectively. Anti-β2GP1-IgG showed highest diagnosis accuracy of APS(AUC=0.908, P<0.05), total aCL was the secondary(AUC=0.904, P<0.05) and anti-(32GP1-IgA was the worst(AUC=0.667, P<0.05). Based on the ROC curve, the sensitivity(86.6%) and specificity(95.9%) of total aCL was the best among the antibody profile. Moreover, total aCL(86.6%) and anti-β2GP1-IgG(82.1%) showed the highest prevalence in APS patients, while anti-β2GP1-IgA(40.3%) showed the lowest.Conclusion:For APS patients, male and PAPS were the risk factor of venous thrombosis, while CTD related APS was the risk factor of arterial thrombosis. Thrombocytopenia was the risk factor of death, and anticoagulation treatment may lessen APS mortality. There shouldn’t be difference between PAPS and SAPS patients for the clinical characteristics of thrombosis event. Previous thrombosis (arterial or venous) event was the risk factor of thrombosis recurrence. Total aCL was the marker that showed the best diagnosis efficacy, sensitivity and specificity in this study.