The atherosclerotic process begins in childhood, with the progression clearly shown to be mediated by the presence of identified risk factors. Studies in children and young adults demonstrate that the extent of the atherosclerotic vascular change is associated with both number of risk factors and their intensity [
Adults with chronic inflammatory disease, specifically patients with rheumatoid arthritis (RA), experience cardiovascular events at a significantly greater incidence than age-matched controls, and cardiovascular disease is reported the major cause of mortality in RA [
There are very scarce published data on subclinical atherosclerosis in patients with JIA, reviewed in [
At present, several noninvasive imaging techniques used in children offer an opportunity to study the relationship of surrogate markers to the development of atherosclerosis. The use of these techniques may help to identify high-risk individuals in preclinical phase who may benefit from active therapy to prevent clinical disease. Endothelial function, that is, the vasodilator response to increased blood flow (flow mediated vasodilatation (FMD)), the analysis of carotid artery intima-media thickness (IMT), and echocardiographic assessment of left ventricle mass and/or hypertrophy (LVM), can now be accomplished using high-resolution ultrasound [
Therefore, the aims of the study were, firstly, to investigate the prevalence of overweight and obesity in children with juvenile idiopathic arthritis and, secondly, to examine possible associations between excess body weight and traditional cardiovascular risk factors together with selected inflammatory markers and early changes in cardiovascular system, which may predispose this group of patients into early clinically symptomatic atherosclerosis. We hypothesized that overweight or obese children and adolescents with JIA had increased surrogate markers of subclinical atherosclerosis in comparison to nonobese JIA patients.
We recruited 58 consecutive JIA children, 32 (55%) girls, aged 7–18 (median 13 years), and diagnosed with juvenile idiopathic arthritis (according to ILAR criteria) for at least one year; they were followed at the tertiary academic center, Medical University of Bialystok, Poland. Oligoarticular, polyarticular, and systemic types of JIA were reported in 28 (48%), 26 (45%), and 4 (7%) patients respectively. Children were divided into clinically active (30–52%) and inactive (28–48%) based on current practice recommendations [
All children underwent physical examination; height and weight were taken in a standard way using the Harpenden stadiometer and digital scale (Seca, Germany). Body mass index (BMI) was calculated with a standard formula. Overweight was determined when the BMI (kg/m2) exceeded the 85th per centile whereas obesity as BMI exceeding the 95th per centile according to national growth references [
A blood sample of 10 mL was taken from the left cubital vein, after an overnight (8–12 hr) fast. To assess inflammatory markers, serum samples were collected, frozen, and stored at the temperature of −80°C until analyses were performed. The concentrations of adiponectin, IL-6, and TNF
The procedure was conducted between 8.00 and 10.00 AM after a fasting period of 8–12 hours. Examinations of the brachial and carotid arteries were performed with Hewlett Packard Sonos 4500 apparatus, using a 7.5 MHz linear transducer. Ultrasound examination of the right brachial arteries was performed in longitudinal sections 2–10 cm above the elbow, according to guidelines [
Measurements of intima-media thickness (IMT) in the common carotid arteries (right and left) were performed as previously described, with own modification [
All participants underwent a complete 2D echocardiogram with M-mode and Doppler study demonstrating structurally normal heart. Measurements of the left ventricle (LV) internal dimension, interventricular septal thickness, and posterior wall thickness were made during diastole according to practice guidelines of the American Society of Echocardiography. Left ventricle mass index (LVMi) was calculated by dividing LV mass by height in meters raised to the power of 2.7 to minimize the effect of age, gender, and body weight [
All the examinations were carried out and analyzed by one experienced pediatric vascular ultrasonographer (AH), who was blinded to the participants’ cardiovascular risk factor status. The intraobserver variability was 2.5% for FMD and 3.2% for IMT (evaluated in a subset of patients,
We obtained approval of the Ethical Committee in the Medical University of Bialystok. Both parents/legal guardians and children gave their written informed consent.
All continuous variables were tested for normal distribution by the Kolmogorov-Smirnov test, with Lilliefors correction and Shapiro-Wilk tests. As most of the studied parameters were not normally distributed, descriptive statistics were calculated as median with the interquartile range: median (IQR). The Mann-Whitney
Demographic characteristics and clinical data are shown in Table
Demographic and clinical characteristics of the juvenile idiopathic arthritis (JIA) patients and the control group.
JIA patients | Control group | |
---|---|---|
Number of patients |
|
|
Age, years | 13.0 (11.0–15.0) | 13.4 (12.0–15.0) |
Gender | ||
Boys | 26 (45%) | 14 (39%) |
Girls | 32 (55%) | 22 (61%) |
Height, meter | 1.5 (1.4–1.7) | 1.6 (1.5–1.7) |
Body mass, kg | 49.0 (33–65) | 51.5 (43–58) |
Age at JIA diagnosis, years | 9.0 (4.5–12.0) | |
Duration of the disease, years | 4.0 (2.0–5.5) | |
Activity of the disease | ||
Clinically active | 30 (52%) | |
Clinically inactive | 28 (48%) | |
Type of the disease | ||
Oligoarticular | 28 (48%) | |
Polyarticular | 26 (45%) | |
Systemic | 4 (7%) | |
Current treatment | ||
Corticosteroids | 42 (72%) | |
Methotrexate | 28 (48%) | |
Biologic agents | 14 (24%) | |
DMARDs | 9 (15%) |
Values are the median (interquartile range) or numbers (%).
The JIA children demonstrated significantly increased SDS-BMI, systolic and diastolic blood pressure, hsCRP, IL-6, TNF
Traditional cardiovascular risk factors, selected inflammatory markers, and ultrasonographic evaluation of cardiovascular system in the juvenile idiopathic arthritis (JIA) patients and the control group.
JIA patients |
Control group |
|
|
---|---|---|---|
Traditional risk factors | |||
| |||
Age, years | 13.0 (11.0–15.0) | 13.4 (12–15) | 0.37 |
BMI, kg/m2 | 20.6 (16.8–22.2) | 19.4 (17.3–20.6) | 0.15 |
BMI-SDS | 0.3 (0.0–0.8) | 0.1 (−0.5–0.5) | 0.03 |
SBP, mm Hg | 117 (102–127) | 112 (103–117) | 0.02 |
DBP, mm Hg | 67 (64–75) | 64 (57–69) | 0.03 |
Total cholesterol, mmol/L | 4 (3.6–4.6) | 4 (3.5–4.4) | 0.60 |
LDL-cholesterol, mmol/L | 2.1 (1.8–2.5) | 2 (1.8–2.4) | 0.63 |
HDL-cholesterol, mmol/L | 1.4 (1.2–1.6) | 1.4 (1.2–1.7) | 0.40 |
Triglycerides, mmol/L | 0.7 (0.6–1) | 0.7 (0.6–0.9) | 0.74 |
Glucose, mmol/L | 4.8 (4.6–5.1) | 4.8 (4.6–5.0) | 0.75 |
Insulin, mU/mL | 7.5 (4.1–11.5) | 6.6 (4.0–8.8) | 0.19 |
HOMA index | 1.5 (0.9–2.4) | 1.4 (0.8–1.9) | 0.19 |
| |||
Inflammatory markers | |||
| |||
hsCRP, mg/L | 1.07 (0.16–3.84) | 0.04 (0.01–0.20) | <0.001 |
Il-6, pg/ml | 2.3 (0.5–6.6) | 0.2 (0.2–0.8) | <0.001 |
TNF |
2.8 (1.0–32) | 0.7 (0.7–0.72) | <0.001 |
Adiponectin, |
11.3 (8.0–14.0) | 12.5 (8.0–16.0) | 0.510 |
| |||
Ultrasonographic studies | |||
| |||
Brachial artery, mm | 3.7 (3.3–4.4) | 3.6 (3.2–4.2) | 0.560 |
FMD, % | 7.8 (5.1–9.1) | 11.1 (9.2–12.6) | <0.001 |
IMT, mm | 0.50 (0.44–0.54) | 0.42 (0.39–0.45) | <0.001 |
LVMi, g/m2.7 | 27.6 (24.5–29.5) | 22.9 (19.2–28.3) | =0.020 |
Values are presented as median (interquartile range), SBP: systolic blood pressure, DBP: diastolic blood pressure, HOMA index: index of insulin resistance, FMD: flow mediated dilatation of the right brachial artery, IMT: intima-media thickness of the common carotid arteries, and LVMi: indexed left ventricle mass.
Children with obesity (OB) had higher BMI and SDS-BMI compared to nonobese or controls (
Traditional cardiovascular risk factors, selected inflammatory markers, and ultrasonographic evaluation of cardiovascular system in nonobese and obese juvenile idiopathic arthritis (JIA) patients.
JIA patients obese |
JIA patients nonobese |
Control group |
|
|
---|---|---|---|---|
Traditional risk factors | ||||
| ||||
Age, years | 13.0 (7.5–15) | 13.0 (11–15.5) | 13.4 (12–15) | 0.580 |
BMI, kg/m2 | 24.0 (21–29)†‡ | 19.0 (16–21) | 19.4 (17.3–20.6) | <0.001 |
BMI-SDS | 3.0 (1.7–4.2)†‡ | 0.06 (−0.2–0.4) | 0.12 (−0.5–0.5) | <0.001 |
SBP, mm Hg | 127 (113–139)† | 117 (101–124) | 112 (103–117) | 0.020 |
DBP, mm Hg | 69 (58–80) | 67 (64–75) | 64 (57–69) | 0.130 |
Total cholesterol, mmol/L | 4.7 (4.3–5.0)†‡ | 3.9 (3.6–4.3) | 4 (3.6–4.4) | 0.010 |
LDL-cholesterol, mmol/L | 2.4 (1.8–2.6) | 2.0 (1.7–2.7) | 2.0 (1.8–2.4) | 0.570 |
HDL-cholesterol, mmol/l | 1.2 (0.9–1.7) | 1.5 (1.3–1.6) | 1.6 (1.2–1.7) | 0.160 |
Triglycerides, mmol/L | 1.3 (0.7–1.5)‡ | 0.7 (0.6–0.9) | 0.7 (0.6–0.9) | 0.040 |
Glucose, mmol/L | 4.8 (4.5–5.1) | 4.8 (4.7–5.1) | 4.8 (4.6–5.0) | 0.690 |
Insulin, mU/mL | 12.4 (11.0–14.3)†‡ | 6.8 (3.8–8.9) | 6.6 (4.0–8.8) | <0.001 |
HOMA index | 2.7 (2.1–3.1)†‡ | 1.5 (0.8–2.0) | 1.45 (0.8–1.9) | =0.001 |
| ||||
Inflammatory markers |
||||
| ||||
hsCRP, mg/L | 5.3 (1.4–7.4)†‡ | 0.6 (0.1–1.6)† | 0.04 (0.01–0.2) | <0.001 |
Il-6, pg/mL | 8.6 (4.4–13.2)†‡ | 1.4 (0.4–4.2)† | 0.2 (0.2–0.8) | <0.001 |
TNF |
3.3 (1–32)† | 2.6 (1–32)† | 0.7 (0.7–0.72) | <0.001 |
Adiponectin, |
12 (11.5–13.6) | 10.5 (6.9–15.6) | 12.5 (8.0–16.0) | =0.570 |
| ||||
Ultrasonographic studies | ||||
| ||||
Brachial artery, mm | 3.8 (3.8–3.9) | 3.6 (3.3–4.2) | 3.6 (3.2–4.2) | =0.520 |
FMD, % | 4.8 (2.7–5.7)†‡ | 8.2 (6.5–9.6)† | 11.1 (9.2–12.6) | <0.001 |
IMT, mm | 0.54 (0.51–0.56)†‡ | 0.48 (0.43–0.53)† | 0.42 (0.39–0.45) | <0.001 |
LVMi, g/m2.7 | 30.2 (27–45)† | 26.8 (21.8–28.5) | 22.9 (19.2–28.3) | =0.003 |
Values are presented as median (interquartile range), obese: group of patients with recognized overweight and obesity, SBP: systolic blood pressure, DBP: diastolic blood pressure, HOMA index: index of insulin resistance, FMD: flow mediated dilatation of the right brachial artery, IMT: intima-media thickness of the common carotid arteries, and LVMi: indexed left ventricle mass.
Subclinical changes in the cardiovascular system in 58 children and adolescents with juvenile chronic arthritis (JIA) divided depending on presence of excess body mass (nonobese JIA, overweight/obese JIA, controls). (a) Intima-media thickness (IMT), (b) endothelial function—flow mediated dilation (FMD), and (c) indexed left ventricle mass (LV mass indexed by height in meters raised to the power of 2.7 to minimize the effect of age, gender, and body weight).
Clinically active disease was associated with higher SDS-BMI compared to controls
Traditional cardiovascular risk factors, selected inflammatory markers, and ultrasonographic evaluation of cardiovascular system in clinically active and inactive juvenile idiopathic arthritis (JIA) patients.
JIA patients clinically active |
JIA patients clinically inactive |
Control group |
|
|
---|---|---|---|---|
Traditional risk factors | ||||
| ||||
Age, years | 12.5 (9.5–15.0) | 14.0 (11.0–16.0) | 13.4 (12.0–15.0) | 0.24 |
BMI, kg/m2 | 20.2 (18.3–22.2) | 20 (16.6–21.7) | 19.4 (17.3–20.6) | 0.19 |
BMI-SDS | 1.1 (0.1–1.7)† | 0.1 (−0.1–0.5) | 0.1 (−0.5–0.5) | 0.01 |
SBP, mmHg | 116 (99–127) | 121 (103–126)† | 112 (103–117) | 0.03 |
DBP, mmHg | 68 (55–71) | 65 (57–69) | 64 (57–69) | 0.20 |
Total cholesterol, mmol/L | 4.2 (3.7–4.7) | 3.9 (3.5–4.4) | 4 (3.5–4.4) | 0.48 |
LDL-cholesterol, mmol/L | 2.2 (1.8–2.5) | 2.0 (1.8–2.5) | 2.0 (1.8–2.4) | 0.71 |
HDL-cholesterol, mmol/L | 1.4 (1.0–1.5) | 1.3 (1.2–1.6) | 1.4 (1.1–1.6) | 0.51 |
Triglycerides, mmol/L | 0.7 (0.6–1.2) | 0.8 (0.5–0.9) | 0.7 (0.6–0.9) | 0.52 |
Glucose, mmol/L | 4.8 (4.6–5.0) | 5.0 (4.8–5.1) | 4.8 (4.6–5.0) | 0.21 |
Insulin, mU/mL | 7.1 (4.8–13.3) | 7.9 (3.8–10.5) | 6.6 (4.0–8.8) | 0.30 |
HOMA index | 1.5 (1.0–2.7) | 1.7 (0.8–2.4) | 1.4 (0.8–1.9) | 0.28 |
| ||||
Inflammatory markers | ||||
| ||||
hsCRP, mg/L | 1.2 (0.3–4.9)† | 0.8 (0.1–2.7)† | 0.04 (0.01–0.2) | <0.001 |
Il-6, pg/mL | 3.6 (1.1–7.4)† | 1.4 (0.4–6.4)† | 0.2 (0.2–0.8) | <0.001 |
TNF |
2.5 (0.8–17.9)† | 3 (1.3–32)† | 0.7 (0.7–0.72) | <0.001 |
Adiponectin, |
10.9 (8.0–13.9) | 11.0 (8.0–14.0) | 12.5 (8.0–16.0) | =0.640 |
| ||||
Ultrasonographic studies | ||||
| ||||
Brachial artery, mm | 3.7 (3.3–3.9) | 3.8 (3.4–4.5) | 3.6 (3.2–4.2) | =0.230 |
FMD, % | 7.8 (6.2–9.6)† | 8.1 (2.7–8.9)† | 11.1 (9.2–12.6) | <0.001 |
IMT, mm | 0.49 (0.43–0.51)† | 0.53 (0.44–0.56)† | 0.42 (0.39–0.45) | <0.001 |
LVMi, g/m2.7 | 27.6 (25.1–29.9)† | 27.6 (18.8–29.1) | 22.9 (19.2–28.3) | =0.040 |
Values are presented as median (interquartile range), SBP: systolic blood pressure, DBP: diastolic blood pressure, HOMA index: index of insulin resistance, FMD: flow mediated dilatation of the right brachial artery, IMT: intima-media thickness of the common carotid arteries, and LVMi: indexed left ventricle mass.
Comparisons between JIA groups according to the type of the disease (oligoarticular, polyarticular, and systemic), regarding cardiovascular risk factors and subclinical markers of atherosclerosis, were not significant (data not shown).
In the group of JIA patients, several significant correlations were found between subclinical markers of atherosclerosis, traditional risk factors for CVD, and inflammatory markers. All analyses are presented in Table
Correlations (Spearman correlation coefficient—rho) between IMT, FMD, LVMi, SDS-BMI, and traditional cardiovascular risk factors and inflammatory markers in the study group.
IMT | FMD | LVMi | SDS-BMI | |
---|---|---|---|---|
BMI | rho = 0.51, |
rho = −0.30, |
rho = 0.38, |
rho = 0.89, |
SDS-BMI | rho = 0.45, |
rho = −0.30, |
rho = 0.43, |
— |
HOMA | rho = 0.29, |
rho = −0.34, |
rho = 0.32, |
rho = 0.41, |
SBP | rho = 0.54, |
rho = −0.20, |
rho = 0.32, |
rho = 0.47, |
DBP | rho = 0.21, |
rho = −0.14, |
rho = 0.04, |
rho = 0.38, |
TC | rho = 0.03, |
rho = −0.10, |
rho = 0.09, |
rho = 0.27, |
LDL | rho = 0.01, |
rho = −0.13, |
rho = 0.06, |
rho = 0.05, |
HDL | rho = −0.36, |
rho = 0.21, |
rho = −0.25, |
rho = −0.35, |
TG | rho = 0.14, |
rho = −0.10, |
rho = 0.23, |
rho = 0.13, |
hsCRP | rho = 0.38, |
rho = −0.3, |
rho = 0.31, |
rho = 0.46, |
IL-6 | rho = 0.35, |
rho = −0.34, |
rho = 0.08, |
rho = 0.36, |
TNF |
rho = 0.36, |
rho = −0.36; |
rho = 0.33, |
rho = 0.02, |
In the multiple regression analysis model taking into account solely the predictive value of traditional risk factors for increased IMT in patients with JIA, SDS-BMI, HOMA, SBP, and DBP were the best predictors, and the model was significant (Table
Multiple linear regression analyses for IMT, FMD, and LVMi as dependent variables.
Model 1 | Model 2 | |||||
---|---|---|---|---|---|---|
Dependent variable | Independent variable |
|
|
Independent variable |
|
|
| ||||||
Age | 0.09 | 0.460 | Age | 0.20 | 0.17 | |
SDS-BMI | 0.25 | 0.010 | SDS-BMI | 0.21 | 0.10 | |
HOMA | 0.18 | 0.050 | HOMA | 0.17 | 0.12 | |
IMT | HDL | −0.16 | 0.070 | HDL | −0.11 | 0.25 |
SBP | 0.42 | 0.001 | SBP | 0.37 | 0.02 | |
DBP | 0.27 | 0.020 | DBP | 0.26 | 0.05 | |
Il-6 | 0.04 | 0.65 | ||||
TNF |
0.20 | 0.04 | ||||
hsCRP | 0.02 | 0.79 | ||||
|
|
|||||
| ||||||
Age | −0.04 | 0.75 | Age | −0.20 | 0.21 | |
SDS-BMI | −0.22 | 0.06 | SDS-BMI | −0.29 | 0.04 | |
HOMA | −0.26 | 0.01 | HOMA | −0.19 | 0.13 | |
HDL | 0.08 | 0.39 | HDL | −0.03 | 0.75 | |
FMD | SBP | −0.01 | 0.80 | SBP | 0.1 | 0.54 |
Il-6 | −0.16 | 0.16 | ||||
TNF |
−0.24 | 0.04 | ||||
hsCRP | −0.04 | 0.71 | ||||
|
|
|||||
| ||||||
Age | −0.01 | 0.880 | Age | 0.02 | 0.890 | |
SDS-BMI | 0.43 | 0.003 | SDS-BMI | 0.53 | 0.004 | |
HOMA | 0.14 | 0.270 | HOMA | 0.07 | 0.620 | |
LVMi | HDL | −0.09 | 0.400 | HDL | −0.01 | 0.880 |
SBP | 0.05 | 0.720 | SBP | 0.02 | 0.860 | |
TNF |
0.20 | 0.100 | ||||
hsCRP | −0.03 | 0.980 | ||||
|
|
Multiple linear regression analyses for IMT, FMD, and LVMi as dependent variables in models of traditional atherosclerosis risk factors (Model 1) and extended model with the conjunction with the inflammatory markers (Model 2), SBP: systolic blood pressure, DBP: diastolic blood pressure, and HOMA: insulin resistance index.
Our main finding is that patients with juvenile chronic arthritis (JIA) had higher body mass, measured as SDS-BMI, although crude values of BMI were similar to those in the control group. Patients with JIA were also characterized by higher systolic and diastolic blood pressure values and increased inflammatory markers. Increased IMT and LVMi and impaired endothelial function, assessed as FMD of brachial arteries, strongly supported the evidence of subclinical changes in cardiovascular system predisposing to early development of clinically symptomatic atherosclerosis.
Interestingly, 22% of children with JIA met the criteria for overweight or obesity relating to updated growth references for Polish children. This group of children appeared to have a number of increased cardiovascular risk factors typically associated with metabolic syndrome (MS): insulin resistance, dyslipidemia, and increased systolic blood pressure, along with increased inflammatory markers such as hsCRP and IL-6 in comparison to nonobese patients and controls. These alterations were associated with increased ultrasonographic markers for early atherosclerosis. To our knowledge, this is the first report concerning the presence of subclinical atherosclerosis in obese individuals with JIA during growth.
The prevalence of obesity in children and adolescents increased substantially in the past decades, with current estimates indicating that 31.7% of children and adolescents in the United States are overweight and 16.9% are obese [
Childhood obesity is associated with established risk factors and accelerated atherosclerosis [
The association between obesity and inflammation in children was first described by Cook et al. who reported much more higher CRP levels in children with excess body mass than in those with normal-weight [
The majority of studies demonstrate that subclinical atherosclerosis, vascular stiffness, and endothelial dysfunction are more prevalent in RA compared to controls [
In adults, increased IMT is an indicator of generalized atherosclerosis and a strong predictor of future cardiovascular events [
In our study, children with JIA had increased indexed left ventricle mass (LVM), and the difference in LVMi between JIA obese and nonobese was also significant. Increased LVM is a recognized predictor of cardiovascular morbidity and mortality [
The present study highlights the importance of obesity in the development of subclinical atherosclerosis in patients with JIA. The increasing research in this area reveals the complex inflammatory-mediated interactions between adipose tissue, cardiometabolic disorders, and rheumatic diseases. Dysregulation of adipokines, presumably resulting from both obesity and rheumatic diseases, might explain some of the subclinical changes in cardiovascular system as early as that in childhood JIA. The cause of adiposity and its complications in general population, but also in JIA, are a combination of negative nutritional habits, overeating, energy imbalance, and physical inactivity. Therefore, the strategy for therapeutic interventions focused on healthy lifestyle is necessary to obtain adequate modulation of inflammatory response and a reduction of cardiovascular risk at early stage of chronic arthritis.
There are certain limitations of our study implicating a careful interpretation of the conclusions; that is, the sample size was relatively small limiting power for analysis or some methodological issues. Furthermore, only nonobese controls were included in the analysis; thus, it would be worth examining the differences between obese, otherwise, healthy children and obese JIA patients. Furthermore, we are aware that our patients were taking medications (glucocorticosteroids or anti-TNF
In conclusion, children and adolescents with JIA demonstrate high overweight and obesity rates. Excess of body weight is associated not only with increased systolic blood pressure, insulin resistance, and dyslipidemia but also with significantly increased levels of inflammatory markers, typical for systemic inflammation in chronic arthritis. Obese JIA patients demonstrate deterioration in cardiovascular system, that is, impaired endothelial function and increased carotid intima-media thickness accompanied by increased left ventricle mass index. This subclinical atherosclerosis depends mainly on obesity-related risk factors; thus, coincidence of the two conditions in childhood may considerably increase CVD risk. Our data show that management of children with JIA, currently focusing on effective treatment and control of the disease activity, should also include individual strategies to maintain appropriate body weight in order to prevent cardiovascular disease in the future.
Body mass index
C-reactive protein
Cardiovascular
Cardiovascular disease
Flow mediated dilation
Enzyme-linked immunosorbent assay
Intima-media thickness
Left ventricle mass index
Soluble intercellular adhesion molecule-1
Tumor necrosis factor.
The authors declare that they have no conflict of interests.
The study was supported by the Polish National Science Centre (Grant no. NN407144639).