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Rationale and design of the screening of pulmonary hypertension in systemic lupus erythematosus (SOPHIE) study.

ABSTRACT: Current guideline-recommended screening for pulmonary hypertension in patients with systemic sclerosis has not been evaluated in systemic lupus erythematosus (SLE), which is disproportionately prevalent in Asians. This multicentre, cross-sectional screening study aims to study the prevalence of pulmonary hypertension among SLE patients using these guidelines, and identify independent predictors and develop a prediction model for pulmonary hypertension in SLE patients. SLE patients from participating centres will undergo an echocardiography- and biomarker-based pulmonary hypertension screening procedure as in the DETECT study. Standard right heart catheterisation will be provided to patients with intermediate or high echocardiographic probability of pulmonary hypertension. Those with low echocardiographic probability will rescreen within 1?year. The primary measure will be the diagnosis and types of pulmonary hypertension and prevalence of pulmonary hypertension in SLE patients. The secondary measures will be the predictors and prediction models for pulmonary hypertension in SLE patients. The estimated sample size is approximately 895 participants. The results of the SOPHIE study will be an important contribution to the literature of SLE-related pulmonary hypertension and may be immediately translatable to real clinical practice. Ultimately, this study will provide the necessary evidence for establishing universal guidelines for screening of pulmonary hypertension in SLE patients.

SUBMITTER: Huang D

PROVIDER: S-EPMC5839606 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Rationale and design of the screening of pulmonary hypertension in systemic lupus erythematosus (SOPHIE) study.

Huang Duo D Cheng Yang-Yang YY Chan Pak-Hei PH Hai Jojo J Yiu Kai-Hang KH Tse Hung-Fat HF Wong Ka-Lam KL Fan Katherine K Li Ying Wah YW Ng Woon-Leung WL Yim Cheuk-Wan CW Wong Cheuk-Hon John CJ Tam Lai-Shan LS Wong Priscilla C H PCH Wong Chi-Yuen CY Ho Chup-Hei CH Leung Alexander M H AMH Mok Chi-Chiu CC Lam Ho H Lau Chak-Sing CS Cheung Tommy T Ho Carmen C Law Sharon W Y SWY Chan Esther W EW Yin Li-Xue LX Yue Wen-Sheng WS Mok Toi Meng TM Evora Mario Alberto MA Siu Chung-Wah CW

ERJ open research 20180101 1

Current guideline-recommended screening for pulmonary hypertension in patients with systemic sclerosis has not been evaluated in systemic lupus erythematosus (SLE), which is disproportionately prevalent in Asians. This multicentre, cross-sectional screening study aims to study the prevalence of pulmonary hypertension among SLE patients using these guidelines, and identify independent predictors and develop a prediction model for pulmonary hypertension in SLE patients. SLE patients from participa ...[more]

PMID: 29531959

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Project description:BackgroundSystemic lupus erythematosus (SLE) is an autoimmune disease that involves multi-organ damage. Pulmonary arterial hypertension (PAH) is one of the life-threatening complications of SLE. The underlying cause of systemic lupus erythematosus-associated pulmonary arterial hypertension has not been fully comprehended. Besides the mechanisms implicated in the development of PAH, such as damage to the endothelial cells, the aberrant activation of the immune system also plays a substantial role in the pathogenesis of SLE-PAH.MethodsIn this study, peripheral blood samples from 100 patients with SLE-PAH and 95 patients of SLE without PAH (SLE-nonPAH) were obtained for RNA sequencing and comprehensive transcriptomic analysis. Pathway enrichment analysis was performed based on differentially expressed genes (DEGs) between SLE-PAH and SLE-nonPAH to elucidate the mechanisms potentially driving the development of PAH in SLE patients. Utilizing consensus non-negative matrix factorization (cNMF), we also conducted a detailed analysis to identify distinct subgroups within the SLE-PAH population. Meanwhile, the protein-protein interaction (PPI) analysis was performed and hub genes among the SLE-PAH subgroups were detected. Common transcription factors (TFs) of detected hub genes were also discovered to serve as potential therapeutic targets.ResultsInflammatory signaling pathways, notably those involving interferon and TNFα, were found to play an important role in the SLE-PAH. Utilizing cNMF method, three unique subgroups of SLE-PAH patients were delineated, each characterized by a distinct level of inflammatory activity. Specifically, the high inflammation subgroup, marked by the activity of Interleukin-6 (IL-6), exhibited a milder form of PAH. In contrast, the subgroup with moderate inflammation displayed the most pronounced PAH symptoms. Further disease enrichment analysis revealed that, beyond the dysregulated inflammatory pathways, patients with the most severe PAH exhibited distinct pathogenic transcriptomic profiles that disrupted vascular smooth muscle homeostasis, a critical component of vascular health. In the most severely affected subgroup, 13 hub genes were identified. Additionally, two transcription factors commonly associated with these genes, KLF1 and GATA1, were discovered, which may serve as potential therapeutic targets.ConclusionOur investigation establishes inflammation as a key driver in the development of SLE-PAH. Patients who presented with concurrent dysregulations in inflammatory responses along with PAH-specific pathogenic markers exhibited a marked increase in the severity of their PAH. The insights gleaned from our transcriptomic analysis reveal the intricate interplay between inflammatory mechanisms and the molecular substrates of PAH. This nuanced understanding paves the way for more targeted and effective therapeutic approaches for SLE-PAH.

Project description:BackgroundPulmonary arterial hypertension is a major cause of death in systemic lupus erythematosus, but there are no tools specialized for predicting survival in systemic lupus erythematosus-associated pulmonary arterial hypertension.Research questionTo 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-min 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.

Project description:Peking Union Medical College Hospital (PUMCH) has started a single-center right heart catheterization (RHC)-based pulmonary arterial hypertension (PAH) study in systemic lupus erythematosus (SLE) since 2006. The baseline characteristics of these patients were described and the risk factor for PAH in lupus was identified.The demographic, clinical, laboratory, and treatment characteristics of SLE patients with PAH when they were registered were collected as the baseline data. A case-control study was conducted by taking the admitted SLE-non-PAH patients adjusted for age and gender in a 4:1 ratio during the same period as the controls. The associated variables were examined by binary multivariate logistic regression analysis to identify possible risk factors. A total of 111 RHC-confirmed SLE-PAH patients were enrolled, with the onset age of 34.6 ± 8.6 years old and the average SLE duration of 5 years. RHC revealed mPAP as 46.4 ± 11.4 mm Hg, CI as 2.7 ± 0.8 L/min × m, and PVR as 10.5 ± 4.8 WU. 46% of patients were WHO Fc I-II. All patients were treated with immunosuppressive agents and 65% patients had PAH-targeted therapy. The case-control study had confirmed 2 independent risk factors previously published: pericardial effusion (OR = 21.290, P < 0.001) and anti-RNP antibody (OR = 12.399, P < 0.001). Meanwhile, 6 independent variables were discovered: baseline SLE duration (OR = 1.118, P = 0.007), interstitial lung disease (OR = 17.027, P < 0.001=, without acute rash (OR = 3.258, P = 0.019), anti-SSA antibody (OR = 4.836, P = 0.004), SLEDAI≤9 (OR = 26.426, P < 0.001), ESR≤20 mm/h (OR = 12.068, P < 0.001), and uric acid > 357 μmol/L (OR = 9.666, P < 0.001) to be associated with PAH in SLE patients.The PUMCH study has shown that SLE patients complicated with PAH are usually earlier diagnosed and have less disease severity than patients without PAH. The immunosuppressive therapy rate and the PAH target therapy rate were high, which is consistent with reports from Western countries. This study has confirmed that pericardial effusion and positive anti-RNP antibody are risk factors for SLE-associated PAH. Long SLE disease duration, the presence of interstitial lung disease, without acute skin rash, positive anti-SSA antibody, low SLEDAI and ESR, and high uric acid levels are also associated with PAH in SLE patients.

Project description:IntroductionPulmonary arterial hypertension (PAH) is a serious complication of systemic lupus erythematosus (SLE) with increased mortality. A prothrombotic state may contribute to pathogenesis of SLE-PAH. Extracellular vesicles (EVs) are known to be associated with thrombosis. Here, we investigated circulating EVs and their associations with SLE-PAH.MethodsEighteen SLE-PAH patients, 36 SLE-non-PAH patients, and 36 healthy controls (HCs) were enrolled. Flow cytometry was used to analyze circulating EVs from leukocytes (LEVs), red blood cells (REVs), platelets (PEVs), endothelial cells (EEVs), and Annexin V+ EVs with membrane phosphatidylserine (PS) exposure.ResultsPlasma levels of all EV subgroups were elevated in SLE patients with or without PAH compared to HCs. Furthermore, plasma Annexin V+ EVs, LEVs, PEVs, REVs, EEVs, and Annexin V+ REVs were significantly elevated in SLE-PAH patients compared to SLE-non-PAH patients. Additionally, PAH patients with moderate/high SLE showed a significant increase in LEVs, PEVs, REVs, Annexin V+ EVs, and Annexin V+ REVs compared to SLE-non-PAH patients. However, PAH patients with inactive/mild SLE only exhibited elevations in Annexin V+ EVs, REVs, and Annexin V+ REVs. In the SLE-PAH patients, EEVs were positively correlated with pulmonary arterial systolic pressure, while PEVs and EEVs were positively correlated with right ventricular diameter. Moreover, the receiver operating characteristic curve indicated that Annexin V+ EVs, LEVs, PEVs, REVs, EEVs and Annexin V+ REVs could predict the presence of PAH in SLE patients. Importantly, multivariate logistic regression analysis showed that circulating levels of LEVs or REVs, anti-nRNP antibody, and serositis were independent risk factors for PAH in SLE patients.DiscussionFindings reveal that specific subgroups of circulating EVs contribute to the hypercoagulation state and the severity of SLE-PAH. Higher plasma levels of LEVs or REVs may serve as biomarkers for SLE-PAH.

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Rationale and design of the screening of pulmonary hypertension in systemic lupus erythematosus (SOPHIE) study.

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Rationale and design of the screening of pulmonary hypertension in systemic lupus erythematosus (SOPHIE) study.

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