第一部分 大动脉炎患者死亡风险和影响因素分析

目的：本研究旨在分析大动脉炎（Takayasu arteritis, TAK）患者的死亡现状和探索影响患者死亡的相关因素。

方法：这项前瞻性多中心队列研究纳入2013 年 7 月至 2021 年 3 月于中国系统性血管炎注册研究登记的 790 名 TAK 患者。研究通过t检验或卡方检验比较死亡组与生存组的临床差异，并通过性别和年龄校正的Cox回归分析TAK患者死亡的影响因素。

结果：在中位随访70个月（IQR 48–100）期间，36例（4.6%）患者死亡，平均死亡年龄42.2±11.7岁。TAK患者10年和20年生存率分别为94.0%和87.7%，主要死因包括心脏并发症（44.4%）、感染（16.7%）和脑血管事件（11.1%）。Cox回归分析示心肌病变（校正HR=9.18，95% CI：1.24–39.45）、肺梗死（校正HR=4.90，95% CI：1.16–20.62）、肾功能不全（校正HR=4.03，95% CI：1.55–10.45）、冠状动脉受累（校正HR=3.55，95% CI：1.39–8.99）、血沉升高（校正HR=3.02，95% CI：1.20–7.65）、肾动脉受累（校正HR=2.52，95% CI：1.15–5.54）和诊断年龄（HR=1.08，95% CI：1.05–1.11）显著增加TAK患者的死亡风险。

结论：心脏并发症是TAK患者的首位死因。诊断年龄增长、肺梗死、冠状动脉受累、心肌病变、肾动脉受累、肾功能不全和血沉升高是TAK患者死亡的危险因素。

第二部分 构建和验证大动脉炎患者心血管事件风险预测模型

目的：本研究旨在分析大动脉炎（Takayasu arteritis, TAK）患者发生心血管事件的相关因素，构建并验证其10年心血管事件风险预测模型。

方法：本项前瞻性队列研究纳入2013 年 7 月至 2021 年 3 月于中国系统性血管炎注册研究中7家研究中心登记的TAK 患者。通过单因素和多因素Cox回归分析TAK患者发生心血管事件的危险因素。根据文献回顾和向前逐步回归筛选预测变量，并通过Cox比例风险模型拟合预测模型。通过区分度（Harrell’s C统计量）和校准度（校准曲线）来评估临床预测模型的预测效能，并运用Bootstrap重抽样法进行内部验证。根据列线图计算的10年心血管事件风险将患者分为低危、中危和高危组，并运用Kaplan-Meier法比较三组患者的心血管事件风险。

结果：本研究纳入702例TAK患者（623名（88.7%）女性），平均诊断年龄为29.2±9.9岁。在中位随访67个月（IQR 46–99）期间，94名（13.4%）患者发生心血管事件。TAK患者的10年心血管事件风险为17.6%。肺部受累（HR=2.30，95% CI：1.14–4.65）、受累动脉数>8（HR=2.01，95% CI：1.32–3.09）、诊断延迟时间>3年（HR=1.67，95% CI：1.05–2.68）、血沉升高（HR=1.75，95% CI：1.12–2.73）和诊断年龄（HR=1.05，95% CI：1.03–1.07）是心血管事件的独立危险因素，并被纳入预测模型。模型的C统计量为0.71（95% CI：0.65–0.77），校准曲线示模型预测的心血管事件风险与实际观察的结果一致。高危组和中危组的心血管事件风险显著高于低危组（P<0.01）。

结论：TAK患者的10年心血管事件风险为17.6%。诊断年龄增长、诊断延迟时间>3年、肺动脉受累、受累动脉数>8和血沉升高可独立增加TAK患者的心血管事件风险。预后模型可用于预测患者10年心血管事件风险和协助临床决策。

第三部分 构建和验证大动脉炎复发风险预测模型

目的：本研究旨在分析大动脉炎（Takayasu arteritis, TAK）患者复发的影响因素，构建和验证TAK复发风险预测模型。

方法：这项前瞻性多中心队列纳入2014年6月至2021年12月于中国系统性血管炎注册研究登记的549名TAK患者。采用单因素和多因素Cox回归分析TAK患者发生疾病复发的相关因素并构建预测模型。根据列线图计算的3年内复发概率将患者分为低危、中危和高危组。通过Harrell’s C统计量和校准曲线来评估模型的区分度和校准度，并通过Bootstrap重抽样法进行内部验证。

结果：在中位随访44个月（IQR 26–62）期间，276例（50.3%）TAK患者出现疾病复发。既往复发史（HR=2.82，95% CI：2.17–3.65）、病程<24月（HR=1.80，95% CI：1.39–2.35）、脑血管事件史（HR=1.57，95% CI：1.13–2.18）、动脉瘤（HR=1.51，95% CI：1.11–2.06）、升主动脉或主动脉弓受累（HR=1.37，95% CI：1.05–1.78）、hsCRP水平升高（HR=1.33，95% CI：1.03–1.72）、受累动脉数目≥6（HR=1.32，95% CI：1.01–1.72）和WBC计数升高（HR=1.30，95% CI：1.02–1.67）是TAK复发的独立危险因素，并被纳入预测模型。预测模型的C统计量为0.70（95% CI：0.67–0.74）。校准曲线示模型预测的复发风险接近实际观察到的结果。中危组和高危组患者的复发风险显著高于低危组（P<0.01）。

结论：疾病复发在TAK患者中很常见。复发风险预测模型有助于识别复发高风险患者并协助临床决策。

Part I Mortality in patients with Takayasu arteritis

Objective: To investigate the mortality as well as the associated factors in patients with Takayasu arteritis (TAK).

Methods: This multicenter study included 790 patients with TAK from the Chinese Registry of Systemic Vasculitis between July 2013 and March 2021. The differences between the deceased group and the survival group were compared by Student t-test or chi-square test, and the factors related to death were explored by Cox regression analysis.

Results: During a median follow-up of 70 (IQR 48–100) months, death was observed in 36 patients (4.6%) with a mean mortality age of 42.2 ± 11.9 years. The 10- and 20-year survival rate in patients with TAK was 94.0% and 87.7%, respectively. The main causes of death were cardiac complications (44.4%), infection (16.7%), and cerebrovascular events (11.1%). Cardiomyopathy (adjusted HR 9.18, 95% CI 1.24–39.45), pulmonary infarction (adjusted HR 4.90, 95% CI 1.16–20.62), renal insufficiency (adjusted HR 4.03, 95% CI 1.55–10.45), coronary artery involvement (adjusted HR 3.55, 95% CI 1.39–8.99), elevated erythrocyte sedimentation rate (adjusted HR 3.02, 95% CI 1.20–7.65), renal artery involvement (adjusted HR 2.52, 95% CI 1.15–5.54), and age at diagnosis (HR 1.08, 95% CI 1.05–1.11) were significantly associated with the increased mortality rate.

Conclusion: Cardiac complication was the leading cause of death in patients with TAK. Advancing age at diagnosis, pulmonary infarction, coronary artery involvement, cardiomyopathy, renal insufficiency, renal artery involvement, and elevated erythrocyte sedimentation rate were risk factors for mortality.

Part II Prediction model for cardiovascular events in patient with Takayasu arteritis

Objective: To analyze the factors associated with cardiovascular events and develop a validated prediction model to predict 10-year cardiovascular events probability in patients with Takayasu arteritis (TAK).

Methods: Patients with TAK were prospectively enrolled from seven clinical centers of the Chinese Registry of Systemic Vasculitis between July 2013 and March 2021. Factors associated with cardiovascular events were assessed by Cox regression analysis. Model performance was measured by Harrell’s concordance index (discrimination) and calibration plots (calibration) and internally validated by Bootstrapping. Nomograms developed by Cox regression were used to calculate the 10-year cardiovascular events probability, and categorized patients into low-, medium-, and high-risk groups.

Results: A total of 702 patients (aged 29.2 ± 9.9 years; 623 [88.7%] women) were included. Cardiovascular events were observed in 94 patients (13.4%) after a median follow-up of 67 (IQR 46–99) months. The 10-year risk for cardiovascular events in patients with TAK was 17.6%. Pulmonary involvement (HR 2.30, 95% CI 1.14–4.65), number of involved arteries over 8 (HR 2.01, 95% CI 1.32–3.09), diagnostic delay over 3 years (HR 1.67, 95% CI 1.05–2.68), elevated erythrocyte sedimentation rate (HR 1.75, 95% CI 1.12–2.73), and age at diagnosis (HR 1.05, 95% CI 1.03–1.07) independently increased the risk of cardiovascular disease and were included in the final model. The Harrell’s concordance index of prediction model was 0.71 (95% CI 0.65–0.77), and the calibration plots suggested predicted outcomes were correlated with the observed outcomes. Both High- and medium-risk patients had a significantly higher rate of cardiovascular events than low-risk patients (P < 0.01).

Conclusion: The 10-year cardiovascular events rate in patients with TAK was 17.6%. Advancing age at diagnosis, diagnostic delay over 3 years, pulmonary involvement, number of involved arteries over 8, and elevated erythrocyte sedimentation rate were risk factors for cardiovascular events. The prediction model performed well in predicting individualized cardiovascular events probability and assisting clinical decision-making.

Part III Prediction model for relapse in patients with Takayasu arteritis

Objective: We aimed to analyze the associated factors and develop a risk prediction model for relapse in patients with Takayasu arteritis (TAK).

Methods: We analyzed the associated factors for relapse in a prospective cohort of 549 TAK patients from the Chinese Registry of Systemic Vasculitis cohort between June 2014 and December 2021 using univariate and multivariate Cox regression analyses. We also developed a prediction model for relapse, and stratified patients into low-, medium-, and high-risk groups. Discrimination and calibration of prediction model were measured using Harrell’s concordance index and calibration plots, and were validated by Bootstrap.

Results: At a median follow-up of 44 (IQR 26–62) months, 276 (50.3%) patients experienced relapses. History of relapse (HR 2.82, 95% CI 2.17–3.65), disease duration < 24 months (HR 1.80, 95% CI 1.39–2.35), history of cerebrovascular events (HR 1.57, 95% CI 1.13–2.18), aneurysm (HR 1.51, 95% CI 1.11–2.06), ascending aorta or aortic arch involvement (HR 1.37, 95% CI 1.05–1.78), elevated high-sensitivity C-reactive protein level (HR 1.33, 95% CI 1.03–1.72), number of involved arteries ≥ 6 (HR 1.32, 95% CI 1.01–1.72), and elevated white blood cell count (HR 1.30, 95% CI 1.02–1.67) at baseline independently increased the risk of relapse and were included in the prediction model. The Harrell’s concordance index of the prediction model was 0.70 (95% CI 0.67–0.74). Predictions correlated with observed outcomes on the calibration plots. Compared to the low-risk group, both medium- and high-risk groups had a significantly higher relapse risk (P < 0.01).

Conclusion: Disease relapse was common in patients with TAK. This prediction model may help to identify high-risk patients for relapse and assist clinical decision-making.