Patient population
Chinese Registry for Systemic Vasculitis (CRSV), based on the CRDC (Chinese Rheumatism Data Center) platform, was developed to collect the clinical information and prognosis data of Chinese patients with systemic vasculitis. The CRSV registry was initiated in July 2013. So far, 118 member centers participated in the registry. Up to April 30, 2019, 1150 patients with TAK were registered in CRSV. All the registered patients must fulfill the 1990 American College of Rheumatology (ACR) classification criteria for Takayasu’s arteritis [8]. Among them, 588 patients were registered and followed-up in Peking Union Medical College Hospital (PUMCH). At the time of registration, computed tomography angiography (CTA) was performed in all patients to confirm the diagnosis and evaluate the extent of artery involvement.
Patients in this study were followed every 1 and 3 to 6 months according to patients’ disease activity status. At each visit, ESR, blood hs-CRP, TNFα, and IL-6 levels were tested. Disease activity was comprehensively assessed based on clinical presentations and Doppler examination results at each visit. Repeated vascular Doppler examinations were performed every 3 to 6 months according to the patient’s disease activity status. Patients with active disease in the first visit were followed-up 1–3 months later. Patients were followed every 6 months if they were assessed to be in inactive disease at the first visit. All patients had vascular Doppler imaging examination at baseline and every follow-up visit.
This study was approved by the Institutional Review Board of Peking Union Medical College Hospital (S-478), Beijing, China. Written informed consent was obtained from all participants, and the study was performed in accordance with the Declaration of Helsinki. Personal information was protected and kept anonymous in CRSV database.
Clinical data
The demographic data and medical histories were collected when patients were registered in CRSV. The clinical manifestations, Birmingham Vasculitis Activity Score (BVAS), Vasculitis Damage Index (VDI) score, laboratory tests (including ESR, serum levels of hsCRP, IL-6, and TNFα), imaging findings (including serial vascular Doppler imaging examination, CTA, etc.), and treatment regimen were recorded at each visit. Outcomes, complications, and adverse events related to medications were recorded if occurred.
Serum levels of IL-6 and TNF-alpha were detected with Siemens LK6P1 and LKNF1 assay kit by IMMULITE/IMMULITE 1000 system at each visit in our center.
Repeated vascular Doppler of carotid arteries, vertebral arteries, subclavian arteries, axillary artery, ulnar and radial artery, abdominal aorta, renal arteries, celiac arteries, and mesangial arteries were performed and compared with former results to identify changes. Since the reconstruction of the vessel wall is a continued process, the changes of vascular images might be found later than that of clinical disease flare. The information of image results was stored in the electronic clinical information system of our center.
Evaluation of disease activity
Disease activity of patient with TAK was evaluated by 2 senior rheumatologists who have more than 5 years of experiences in taking care of TAK patients. They were responsible for judging the disease activity based on comprehensive assessment of clinical manifestations and serial vascular Doppler imaging findings at each visit. In this study, all vascular examinations were performed by 2 vascular Doppler specialists who had ever been trained for large vessel Doppler examination. They were blind to the lab test results of patients. The “image active disease” was defined as new occurrence of stenosis or occlusion or dilatation (including aneurysm), worsen mural thickness or stenosis. The definition of active disease was also defined as the presence of the following symptoms or signs after other causes were excluded (“clinical active disease”): fever, weight loss, fatigue and/or arthralgia/arthritis/myalgia, new onset or aggravated symptoms of ischemia (including limb claudication, stroke, dizziness, syncope, severe abdominal pain, myocardial infarction, or angina), acute visual symptoms such as amaurosis fugax or diplopia, new onset hypertension, new onset of vessel bruit, new loss of pulses, carotidynia or tenderness of vessels, and other conditions judged by the 2 senior rheumatologists that increase the dosage of corticosteroid and/or necessary addition of immunosuppressive drugs. Patients with any among “clinical active disease”, “image active disease”, or judged by the rheumatologist as active were defined as “active disease.” If the patient had none of the clinical manifestations for active disease and did not have active image presentations, or judged by the rheumatologist as in inactive disease, then the patient was defined as “inactive disease.” Flare was defined when the patient’s disease status changed from “inactive disease” to “active disease,” and remission was defined when the patient’s disease status changed from “active disease” to “inactive disease.”
Visits during follow-up
The visit when all the above blood parameters were tested and data were collected from serial vascular Doppler imaging examination for future comparison was defined as the baseline visit. Then, patients were followed-up at 1- and 3 to 6-month intervals depending on the patient’s situation and disease activity status was evaluated by the 2 rheumatologists. At each follow-up visit, comprehensive history taking and physical examination were done, all the parameters were tested, and vascular Doppler imaging examination was repeated every 3 to 6 months.
Statistical analysis
Continuous variables were expressed as the mean ± standard deviation for the data in a normal distribution and median (quantile 1, quantile 3) for the non-normal distributed data. Kolmogorov-Smirnov test was used to test data normality. If normal distribution was satisfied, t test was used to compare between groups. Categorical variables were expressed as absolute numbers and percentages, and chi-squared test was used to compare between groups.
In our analysis, serum level of TNFα was categorized into normal and abnormal groups by the upper limit of normal range in healthy population (≤ 8.1 pg/ml), so was serum level of IL-6 (upper limit of normal range ≤ 5.9 pg/ml), hsCRP (upper limit of normal range ≤ 8 mg/L), and ESR (upper limit of normal range ≤ 20 mm/1st hour).
The univariate logistic regression analysis was performed to investigate the association between these parameters (ESR, hsCRP, IL-6, and TNFα) and disease activity at baseline. Furthermore, sensitivity, specificity, and the 95% confidence intervals were calculated. For follow-up data, univariate Cox regression model was used to explore the association of ESR, hsCRP, IL-6, and TNFα with disease activity in the follow-up visits. Positive predictive values and negative predictive values, as well as the 95% confidence intervals were also represented. Kaplan-Meier method was conducted to describe the curve of cumulative remission rate, and log-rank tests were used to compare cumulative remission curves.
For patients with active disease at baseline but turned inactive during follow-up, the follow-up time in survival analysis was the duration from the date of baseline visit to the date of visit when inactive disease was first achieved. For those patients who were still in active state in later follow-up visits, their follow-up time was defined from the date of baseline visit to the end of the study.
For patients who were in inactive disease at baseline but changed to active diseases during follow-up, their follow-up duration was defined from the date of baseline visit to the date of visit for first relapse. For patients who remained in inactive during follow-up, their follow-up duration was defined from the date of baseline visit to the end of the study.
A two-sided p value less than 0.05 was considered to be statistically significant, and the odds ratio (OR) or hazard ratio (HR) with a 95% confidence interval (CI) were also calculated. Analysis was performed with the SAS software (version 9.0, SAS Institute, Cary, NC, USA).