SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES

Objective

Chronic inflammatory diseases in adults have been associated with increased cardiovascular risk and impaired vascular function. We aimed to assess the presence of early vascular dysfunction in patients with juvenile idiopathic arthritis (JIA) and investigate the role of inherent inflammatory process of JIA in vascular health.

Methods

Thirty patients with JIA (age range 7–18 years) were compared to 33 age- and sex-matched controls. Endothelial function (brachial artery flow-mediated dilation [FMD]), carotid intima-media thickness (IMT), and arterial stiffness were examined. Endothelial inflammation was assessed by intercellular adhesion molecule 1 (ICAM-1) and P-selectin measurements.

Results

Patients with JIA showed decreased FMD compared to controls (P = 0.001), independent of age (P = 0.9 among age subgroups). Baseline differences in erythrocyte sedimentation rate, ICAM-1, and glucose between the 2 groups accounted for the difference in FMD. The presence of systemic JIA was associated with greater IMT compared to patients with oligoarticular disease, polyarticular disease, or controls (P = 0.014, P = 0.069, and P = 0.046, respectively). The difference in IMT between systemic versus oligoarticular/polyarticular JIA was attributed to the following risk factors: age, body mass index, blood pressure, disease activity, and corticosteroids use. There were no differences in arterial stiffness indices between JIA patients and controls or between patients with systemic versus nonsystemic disease.

Conclusion

Endothelial function is impaired in patients with JIA at a very young age, while IMT is increased only in the presence of systemic JIA. Vascular dysfunction may be partly attributed to the effects of disease-related characteristics (inflammation, disease activity, and medications).


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES

Cardiovascular diseases (CVDs) are the primary cause of mortality in chronic inflammatory diseases (CIDs) in adult populations, an observation that cannot be explained by the effects of traditional risk factors alone (1). There are several similarities between the inflammatory and immune mechanisms of the atherosclerotic process, the major substrate of CVD and CID (2). Hence, it has been suggested that CID may be associated with a high risk for development of atherosclerosis early in the course of the disease, leading to increased incidence of CVD in the long term (3). Noninvasive assessment of early functional and structural atherosclerotic changes in the vascular wall enables the detection of subclinical vascular dysfunction long before the occurrence of clinical cardiovascular events. Indices of subclinical atherosclerosis, such as impaired flow-mediated dilation (FMD) in the brachial artery, increased carotid intima-media thickness (IMT), and arterial stiffness, have been associated with worse cardiovascular prognosis in adults (4–6). In contrast, few data are available regarding the prognostic role of these techniques in pediatric populations (3, 7).

Juvenile idiopathic arthritis (JIA) is one of the most common inflammatory disorders of the joints in children, with onset before the age of 16 years, and JIA may persist for many years in adult life (8). It has been shown to be a heterogeneous disorder with markedly distinct pathogenesis between the oligoarticular, polyarticular (synovial inflammation), and systemic (multisystem inflammation) types (9). The association of JIA with increased incidence of premature atherosclerosis and a possible increased future cardiovascular risk has not been adequately investigated. In adult populations with CID, indices of subclinical atherosclerosis have been well documented (10–12) and related to worse cardiovascular prognosis (1, 12). In patients with CID, vascular dysfunction appears to occur at a relatively young age (13, 14). However, there are limited data on indices of premature atherosclerosis (15, 16) in patients with JIA. Elevated levels of proinflammatory adhesion molecules associated with endothelial activation have also been reported in patients with JIA and have been related to disease activity (17, 18).

The aim of the present study was to assess the presence of vascular dysfunction in children and adolescents with JIA compared to age- and sex-matched healthy controls and investigate the role of inherent inflammatory process in vascular health.

Significance & Innovations

  • Rheumatoid arthritis is associated with increased cardiovascular risk and impaired indices of subclinical atherosclerosis in adult populations. However, studies in children with juvenile idiopathic arthritis (JIA) are lacking.

  • A complete evaluation of subclinical atherosclerosis including assessment of endothelial function (flow-mediated dilation [FMD]), carotid intima-media thickness (IMT), and arterial stiffness (carotid-femoral pulse wave velocity, large and small artery elasticity indices) in children and adolescents with JIA has not been previously reported.

  • FMD is moderately impaired in children/adolescents with JIA compared to healthy age- and sex-matched controls. IMT is increased only in patients with systemic JIA compared to patients with oligoarticular/polyarticular JIA or controls.

  • Further research in larger populations is needed to assess: 1) the prognostic implications of these findings, 2) the importance of various disease phenotypes, and 3) the impact of different kinds of treatment on cardiovascular risk in children and adolescents with JIA.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES

Study population.

Thirty children and adolescents diagnosed with JIA attending the outpatient Rheumatology Clinic of the Pediatrics Department of the University Hospital of Ioannina, Greece, were sequentially recruited between January 2009 and March 2010. Inclusion criteria were ages 7–18 years and a diagnosis of JIA according to the International League of Associations for Rheumatology criteria (8) before the age of 16 years, with at least 6 months' followup before the establishment of diagnosis after the exclusion of other related diseases. Oligoarticular, polyarticular, and systemic types of JIA were reported in 15, 8, and 7 children, respectively. Duration of JIA was recorded as the time in months since the first visit of the child in the outpatient clinic. Disease activity was evaluated based on the following features: Ritchie Articular Index, swollen joint count, tender joint count, erythrocyte sedimentation rate (ESR), and general health (19). JIA patients were classified as having active or inactive disease. An inactive disease diagnosis required that the patient did not have active synovitis, active uveitis, fever, rash, serositis, splenomegaly, generalized lymphadenopathy attributable to JIA, or elevated ESR, while the physician's global assessment of disease activity indicated no active disease (19). All other cases were classified as active disease. Duration of active disease was estimated as the sum of time not being in remission (19) as recorded in the patient's history. Twenty-six patients (87%) were receiving treatment for the control of active disease as determined in previous visits; 3 patients (10%) were taking nonsteroidal antiinflammatory drugs (NSAIDs), 4 patients (13%) were taking corticosteroids, 9 (30%) were taking anti–tumor necrosis factor (anti-TNF) agents, and 15 (50%) were receiving methotrexate (MTX). Healthy age- and sex-matched children and adolescents (n = 33), who presented at the Emergency Pediatrics Department of the University Hospital of Ioannina, Greece, served as controls if, at the end of a complete medical and laboratory examination, nothing significant was revealed.

No participant was overweight, obese, or had a history of hypertension, dyslipidemia, diabetes mellitus, or CVD. All participants were lifelong nonsmokers and had no family history for hypercholesterolemia and premature coronary heart disease in first-degree relatives. Other concomitant illnesses like anemia, infections, malabsorption, endocrine, renal, and metabolic diseases were excluded. Children and adolescents in the control group were not taking any regular medication, while the patients with JIA did not receive any other treatment unrelated to their disease. Written informed consent was obtained from the parents, and the participants provided assent. The study was approved by the Ethics Committee of the University Hospital of Ioannina and complied with the Declaration of Helsinki.

Study design.

This was a cross-sectional study investigating differences in vascular function indices between children and adolescents with JIA and healthy age- and sex-matched controls. All participants underwent a complete clinical evaluation including measurement of weight, height, and brachial blood pressure. Body mass index (BMI) was calculated using the formula: weight (kg)/height (m2). Blood samples were drawn early in the morning after overnight fasting, and vascular studies were performed the next day at the Michaelidion Cardiac Centre, University of Ioannina, Greece.

Laboratory measurements.

Hemoglobin level, white blood cell count, and creatinine level were determined by standard methodology (Sysmex Corporation and Roche Diagnostics). ESR was analyzed by the Westergren method. Serum high-sensitivity C-reactive protein (CRP) level was measured using rate turbidimetry (IMMAGE Immunochemistry Systems and Calibrator 5 Plus, Beckman Coulter). Fasting levels of total and high-density lipoprotein (HDL) cholesterol, triglycerides, and glucose were determined by standard automated methods on the Olympus AU640 Clinical Chemistry Analyzer (Olympus Diagnostica). Low-density lipoprotein (LDL) cholesterol was calculated using the Friedewald formula: LDL cholesterol = total cholesterol − HDL cholesterol − (triglycerides/5).

Intercellular adhesion molecule 1 (ICAM-1) and P-selectin were measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits (Bender MedSystems), according to the manufacturer's instructions. Reproducibility within each of the previous assays was evaluated in independent experiments and the intraassay coefficient of variation was 4.1% and 7.8% for soluble ICAM-1 and P-selectin ELISA, respectively. Blood samples destined for the measurement of proinflammatory molecules were centrifuged at 3,500 rpm for 10 minutes within 1 hour of collection and serum was stored at −80°C until analysis.

Vascular studies.

All studies were performed in the morning, with the participants having fasted for at least 6 hours and prior to engaging in any strenuous physical activity. All measurements were taken in the supine position in a quiet, temperature-controlled room (∼22°C) after a 20-minute period of rest. Initially, measurement of FMD and IMT were performed by the same operator and, subsequently, arterial stiffness indices were assessed by another operator. The operators (PT, AB, and KV) were blinded to the disease status of the children.

Ultrasound vascular studies.

An echo Doppler ultrasound (Ultrasound ATL, HDI 5000, Bothell) and a 5–12 MHz transducer were used for optimal imaging of the brachial and common carotid arteries.

Brachial artery protocol.

Endothelial function was assessed in all participants by measurement of endothelium-dependent vasodilation in the right brachial artery in response to hand hyperemia, based on previously described methodology (20), according to recently published recommendations in children and adolescents (7). Images were acquired at baseline and every 30 seconds from the first to the third minute after deflation of a wrist cuff inflated to ∼250 mm Hg for 4 minutes for measurement of FMD. Brachial artery blood flow was measured by continuous wave Doppler at baseline and 15 seconds after cuff release. FMD was calculated as the maximum percent increase in arterial diameter during the first 3 minutes of hyperemia compared with the diameter at rest.

Carotid artery protocol.

Common carotid artery (CCA) IMT measurement was performed in all participants using a standardized protocol published previously (20), based on recently published recommendations in children and adolescents (7). Three consecutive longitudinal images of each CCA 1–2 cm proximal to the bifurcation were acquired. Measurements were always made at the far wall of the artery. The mean value of IMT for right and left CCA was obtained by averaging the 3 measurements at each artery. Finally, the mean carotid IMT of the CCAs was determined.

Off-line analysis and measurement of brachial artery end diastolic diameter and IMT were performed by another blinded operator by means of the software QLAB (Philips Ultrasound, Bothell) with manual and automatic (for brachial and carotid artery, respectively) determination of the relative vascular wall margins. Measurements were made at end diastole coincident with the R wave on electrocardiogram. In studies performed on 2 separate days (7–10 days apart) in 10 subjects by a single operator, the within-subject coefficient of variation of FMD and IMT was 6.9% and 1.5%, respectively.

Arterial stiffness indices.

Pulse wave velocity (PWV).

Aortic PWV was measured noninvasively with the commercially available Sphygmocor system (version 7.01, AtCor Medical). Using applanation tonometry, pressure waveforms were recorded from the carotid and femoral arteries. Wave transit time (t) was calculated by the system software, using the R wave on the simultaneously recorded electrocardiogram as a reference frame. The distance traveled by the pulse wave was measured over the body surface as the distance between the 2 recording sites, and the distance from the suprasternal notch to the carotid was subtracted. PWV was calculated as distance/transit time.

Arterial compliance measurements.

The large artery elasticity index (LAEI) and small artery elasticity index (SAEI) were obtained by an HDI/Pulsewave CR-2000 Cardiovascular Profiling System (Hypertension Diagnostic) as previously described (21). This methodology is based on diastolic pulse contour analysis and uses a modified Windkessel model to derive information on proximal and distal arteries by analyzing the diastolic portion of the pressure pulse contour. To convert values to whole numbers, the units for LAEI (ml × mm Hg − 1) were multiplied by 10 and the units for SAEI (ml × mm Hg − 1) were multiplied by 100. An appropriately sized blood pressure cuff was placed around the subject's left upper arm, and a rigid wrist stabilizer was placed on the subject's right wrist to minimize wrist movement and stabilize the radial artery during the measurement.

In studies performed on 2 separate days (8–12 days apart) in 12 subjects by a single operator, the within-subject coefficient of variation of PWV, LAEI, and SAEI was 5.6%, 6.8%, and 9.1%, respectively.

Statistical analysis.

Continuous data are presented as mean ± SD. Kolmogorov-Smirnov Z test was used to determine the normal distribution of all continuous variables; CRP level, ESR, creatinine level, and ICAM-1 were not normally distributed. Independent-samples t-test and chi-square test were used to compare continuous and categorical variables, respectively, between patients with JIA and healthy controls and between JIA patients with systemic and nonsystemic disease. For non–normally distributed continuous variables, the Mann-Whitney U test was used. Differences in FMD between control and JIA patients, and also in IMT, BMI, HDL, and blood pressure between subgroups of JIA patients (systemic, oligoarticular, and polyarticular disease) were adjusted for baseline differences using univariate general linear model analysis. To investigate whether the difference in FMD observed between groups was age dependent, children were divided into 3 age subgroups: 1) 7–10 years, 2) 11–13 years, and 3) >13 years. Two-way analysis of variance (ANOVA) was used to assess a potential effect of the interaction of disease status (JIA versus control) and age group on FMD. One-way ANOVA was used to compare studied parameters among the 3 groups of disease type (oligoarticular, polyarticular, and systemic) in patients with JIA, as well as IMT values among the 3 JIA subgroups and controls. P values were always 2-sided and a value less than 0.05 was considered significant. Statistical analysis was performed using SPSS, version 15.0 for Windows.

Power analysis was based mainly on previously published studies in pediatric populations (7) and unpublished data from our work in dyslipidemic children, since studies in JIA populations are lacking (15, 16). We assumed that changes in vascular health in children and adolescents with JIA would not be severe given the young age and the lack of other cardiovascular risk factors. Therefore, it was calculated that a sample of 26 in each group would render 95% power to detect differences in vascular parameters between groups that equal 1 SD of our measurements (i.e., differences of 2.5% in FMD, 1.0 meters/second in PWV, 0.03 mm in IMT, 6.0 ml/mm Hg in LAEI, and 3.0 ml/mm Hg in SAEI based on preliminary data in children with JIA and dyslipidemic children in our laboratory).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES

Comparison between patients with JIA and healthy controls.

The demographic, clinical, laboratory, and vascular data of patients with JIA and healthy controls are shown in Table 1. The two groups were well matched for age, sex, and BMI. Patients with JIA had significantly higher ESR (P = 0.007) and ICAM-1 (P < 0.001) and showed a trend towards higher glucose levels (P = 0.053). Decreased FMD values (P = 0.001) were observed in JIA patients compared to controls. After adjustment for ESR, ICAM-1, and glucose that differed between groups, these differences in FMD were no longer significant (P = 0.054). No differences in IMT, PWV, LAEI, and SAEI were found between groups. Two-way ANOVA showed that the difference in FMD between controls and patients with JIA was not affected by age and was similar in the 3 age subgroups studied (P = 0.9) (Figure 1).

Table 1. Demographic, clinical, laboratory, and vascular data in children with JIA and controls*
 JIA group (n = 30)Control group (n = 33)P
  • *

    Values are the mean ± SD unless indicated otherwise. JIA = juvenile idiopathic arthritis; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; HDL = high-density lipoprotein; LDL = low-density lipoprotein; ICAM-1 = intercellular adhesion molecule 1.

  • Statistically significant, P < 0.05.

Age, years12 ± 312 ± 20.4
Male sex, no. (%)9 (30)12 (36)0.6
Weight, kg47 ± 1445 ± 90.6
Height, cm151 ± 16154 ± 120.4
Body mass index, kg/m219.9 ± 3.118.9 ± 2.40.2
Hemoglobin, gm/dl13.2 ± 1.213.1 ± 0.90.6
White blood cells,/μl6,855 ± 1,4616,471 ± 1,2160.3
ESR, mm/hour19 ± 218 ± 40.007
CRP level, mg/dl4.2 ± 6.91.7 ± 0.70.1
Glucose, mg/dl87 ± 783 ± 110.053
Creatinine, mg/dl0.72 ± 0.140.71 ± 0.080.9
Total cholesterol, mg/dl164 ± 29165 ± 160.9
HDL cholesterol, mg/dl51 ± 1256 ± 120.2
Triglycerides, mg/dl71 ± 2264 ± 130.1
LDL cholesterol, mg/dl98 ± 2896 ± 170.8
Systolic blood pressure, mm Hg109 ± 11112 ± 100.2
Diastolic blood pressure, mm Hg58 ± 759 ± 70.6
ICAM-1, ng/ml858 ± 263645 ± 147< 0.001
P-selectin, ng/ml165 ± 93136 ± 740.2
Baseline brachial artery diameter, mm2.92 ± 0.493.03 ± 0.460.4
Flow-mediated dilation, %7.10 ± 2.239.93 ± 3.900.001
Intima-media thickness, mm0.46 ± 0.030.45 ± 0.030.4
Aortic pulse wave velocity, meters/second5.5 ± 0.95.7 ± 1.00.3
Large artery elasticity index, ml/mm Hg12.5 ± 5.912.9 ± 6.10.8
Small artery elasticity index, ml/mm Hg6.8 ± 3.06.8 ± 2.81.0
thumbnail image

Figure 1. The impairment in brachial flow-mediated dilatation (FMD) in patients with juvenile idiopathic arthritis (JIA) compared to controls was similar among the 3 age subgroups studied (P = 0.055, P = 0.057, and P = 0.069 between patients with JIA and controls ages 7–10 years, 11–13 years, and >13 years, respectively) (P = 0.9, two-way analysis of variance for the effect of age on FMD differences between patients with JIA and controls).

Download figure to PowerPoint

Analysis in patients with JIA.

The mean ± SD duration of disease and active disease was 79 ± 45 months (range 6–162 months) and 58 ± 49 months (range 1–161 months), respectively, in all JIA patients. Twenty-one (70%) patients with JIA had active disease at study entry. No differences in any studied parameters, including vascular markers, were observed between children with active and nonactive disease (Table 2). Vascular parameters did not differ according to the use of NSAIDs, MTX, or anti-TNF agents. Treatment with corticosteroids was associated with higher PWV, LAEI, and SAEI values (P < 0.05 for all); these differences were lost after adjustment for age between patients taking and patients not taking corticosteroids (P > 0.05 for all) (data not shown).

Table 2. Demographic, clinical, laboratory, and vascular data in patients with JIA according to disease activity*
 Active (n = 21)Inactive (n = 9)P
  • *

    Values are the mean ± SD unless indicated otherwise. P value for comparisons between groups using unpaired t-test for continuous variables and chi-square test for dichotomous variables. JIA = juvenile idiopathic arthritis; NSAIDs = nonsteroidal antiinflammatory drugs; anti-TNF = anti–tumor necrosis factor; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; HDL = high-density lipoprotein; LDL = low-density lipoprotein; ICAM-1 = intercellular adhesion molecule 1.

Age, years12 ± 313 ± 20.8
Male sex, no. (%)7 (33)2 (22)0.7
Body mass index, kg/m220.05 ± 3.3719.60 ± 2.420.7
Disease duration, months78 ± 4683 ± 440.8
Active disease duration, months59 ± 5255 ± 420.8
Treatment, no. (%)   
 NSAIDs2 (10)1 (11)1.0
 Corticosteroids3 (14)1 (11)1.0
 Methotrexate11 (52)4 (44)1.0
 Anti-TNF agents7 (33)2 (22)0.7
ESR, mm/hour21 ± 2514 ± 100.4
CRP level, mg/dl5.2 ± 8.11.7 ± 1.00.08
Glucose, mg/dl87 ± 789 ± 70.4
Creatinine, mg/dl0.70 ± 0.130.78 ± 0.150.2
Total cholesterol, mg/dl166 ± 31157 ± 250.4
Triglycerides, mg/dl69 ± 1576 ± 340.6
HDL cholesterol, mg/dl51 ± 1353 ± 90.6
LDL cholesterol, mg/dl102 ± 3089 ± 210.2
Systolic blood pressure, mm Hg109 ± 11109 ± 121.0
Diastolic blood pressure, mm Hg57 ± 759 ± 70.5
ICAM-1, ng/ml865 ± 257842 ± 2920.8
P-selectin, ng/ml172 ± 86148 ± 1100.5
Flow-mediated dilation, %7.14 ± 2.357.01 ± 2.060.9
Intima-media thickness, mm0.46 ± 0.030.45 ± 0.030.3
Aortic pulse wave velocity, meters/second5.55 ± 2.915.35 ± 2.920.6
Large artery elasticity index, ml/mm Hg11.4 ± 5.414.9 ± 6.60.1
Small artery elasticity index, ml/mm Hg6.3 ± 3.08.2 ± 2.50.1

One-way ANOVA showed that there was a difference in IMT (P = 0.013) among children with oligoarticular, polyarticular, or systemic disease. No differences in other vascular indices (FMD, PWV, LAEI, or SAEI) were observed among the 3 groups of disease type (Table 3). Post hoc analysis showed that IMT was significantly increased in patients with systemic compared to oligoarticular disease (P = 0.014); IMT was also higher in systemic compared to polyarticular disease, although this did not reach statistical significance (P = 0.069). There were also significant differences in BMI, treatment with corticosteroids, and diastolic blood pressure (P < 0.05 for all) among the 3 groups of patients, while there was a trend (although not statistically significant) for a difference in age, systolic blood pressure, HDL cholesterol, and disease activity among groups (Table 3). Interestingly, the differences in BMI, HDL cholesterol, and systolic and diastolic blood pressure among subgroups were attributed to the increased use of corticosteroids in patients with systemic JIA (P > 0.05 after adjustment for steroid treatment). The difference in IMT among patients with oligoarticular, polyarticular, and systemic JIA was lost (P = 0.114) after adjustment for baseline subgroup differences in age, BMI, blood pressure, lipids, disease activity, and corticosteroids treatment. IMT was also increased in patients with systemic JIA compared to healthy controls (P = 0.046), while it did not differ between patients with oligoarticular or polyarticular JIA and controls (P = 1.0 for both) (Figure 2).

Table 3. Demographic, clinical, laboratory, and vascular data according to type of JIA*
 Oligoarticular (n = 15)Polyarticular (n = 8)Systemic (n = 7)P
  • *

    Values are the mean ± SD unless indicated otherwise. P value for comparisons between groups using one-way analysis of variance for continuous variables and chi-square test for dichotomous variables. JIA = juvenile idiopathic arthritis; NSAIDs = nonsteroidal antiinflammatory drugs; anti-TNF = anti–tumor necrosis factor; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; HDL = high-density lipoprotein; LDL = low-density lipoprotein; ICAM-1 = intercellular adhesion molecule 1.

  • P < 0.05 versus patients with oligoarticular JIA in post hoc analysis (Bonferroni test).

  • Statistically significant, P < 0.05.

Age, years11 ± 313 ± 214 ± 20.080
Male sex, no. (%)4 (27)2 (25)3 (43)0.7
Body mass index, kg/m218.54 ± 3.1819.94 ± 1.8122.84 ± 2.000.006
Disease duration, months75 ± 42104 ± 4062 ± 490.2
Active disease duration, months52 ± 4284 ± 5140 ± 540.2
Active disease, no. (%)10 (67)4 (50)7 (100)0.095
Treatment, no. (%)    
 NSAIDs3 (20)0 (0)0 (0)0.2
 Corticosteroids1 (7)0 (0)3 (43)0.029
 Methotrexate9 (60)3 (38)3 (43)0.5
 Anti-TNF agents3 (20)4 (50)2 (29)0.3
ESR, mm/hour18.5 ± 24.021.3 ± 14.617.6 ± 24.90.9
CRP level, mg/dl4.8 ± 8.93.9 ± 5.83.1 ± 2.50.8
Glucose, mg/dl88 ± 786 ± 688 ± 90.9
Creatinine level, mg/dl0.74 ± 0.140.73 ± 0.070.69 ± 0.200.7
Total cholesterol, mg/dl167 ± 20164 ± 26149 ± 300.3
Triglycerides, mg/dl74 ± 2870 ± 1467 ± 150.8
HDL cholesterol, mg/dl56 ± 1146 ± 947 ± 130.061
LDL cholesterol, mg/dl96 ± 19104 ± 2088 ± 310.4
Systolic blood pressure, mm Hg104 ± 9112 ± 11115 ± 130.062
Diastolic blood pressure, mm Hg55 ± 662 ± 7,01359 ± 50.025
ICAM-1, ng/ml929 ± 243711 ± 129875 ± 3690.2
P-selectin, ng/ml177 ± 93131 ± 71179 ± 1150.5
Flow-mediated dilation, %7.42 ± 2.506.68 ± 2.386.91 ± 2.540.7
Intima-media thickness, mm0.45 ± 0.020.45 ± 0.030.49 ± 0.020.013
Aortic pulse wave velocity, meters/second5.3 ± 0.75.3 ± 1.06.0 ± 1.10.3
Large artery elasticity index, ml/mm Hg12.8 ± 7.410.8 ± 3.313.7 ± 4.70.6
Small artery elasticity index, ml/mm Hg7.3 ± 3.25.2 ± 2.67.8 ± 2.40.2
thumbnail image

Figure 2. Children with systemic juvenile idiopathic arthritis (JIA) demonstrate greater intima-media thickness compared to children and adolescents with oligoarticular/polyarticular JIA and controls.

Download figure to PowerPoint

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES

Children and adolescents with JIA demonstrate moderately impaired endothelial function, as assessed by reduced brachial FMD compared to age-matched healthy controls, an effect consistent in all age subgroups and clinical phenotypes of disease. IMT was found to be increased only in patients with systemic JIA compared to either controls or children with oligoarticular or polyarticular disease. No differences in arterial stiffness indices were demonstrated in JIA patients compared to controls or among JIA patients with systemic, oligoarticular, or polyarticular disease.

Endothelial dysfunction, detected early in the atherosclerotic process, is known to play an important role in the initiation and progression of atherosclerosis (22). Decreased brachial FMD has been associated with increased long-term incidence of cardiovascular events in healthy adults or CVD patients (6). Decreased FMD has also been demonstrated in children/adolescents at high CVD risk such as children/adolescents with type 1 diabetes mellitus, familial hyperlipidemia, or obesity (7). This was the first study to indicate reduced FMD in children/adolescents with JIA compared to controls (by ∼30%) independent of the patient's age, indicating an increased cardiovascular risk even at the age of 7–8 years. Endothelial dysfunction was deteriorated to a similar extent in patients with systemic and nonsystemic JIA. Impaired FMD has been consistently observed in adult patients with CID, such as rheumatoid arthritis (11, 13), as well as in children with Kawasaki disease (23), a systemic vasculitis that occurs mainly in younger ages. Recently, no difference in FMD between children/adolescents with systemic lupus erythematosus and healthy controls (24, 25) was reported.

In our study, endothelial dysfunction in patients with JIA was attributed partly to increased levels of inflammatory markers (ICAM-1 and ESR) compared to controls, suggesting an association between systemic inflammation and impaired endothelial function in JIA patients. Increased levels of CRP, ESR, and ICAM-1 have been previously documented in JIA and related to disease activity, but have not been directly related to endothelial dysfunction or atherosclerosis progression (17, 18). In adults with CID, increased levels of inflammatory markers have been related to adverse cardiovascular prognosis (26), endothelial dysfunction (27), and subclinical atherosclerosis (26–28).

Differences in glucose levels between the 2 groups were also in part responsible for the observed differences in FMD. Of note, these differences were very small (higher levels in patients with JIA by ∼4 mg/dl) and glucose levels were within normal limits in both groups. Increasing glucose levels have been shown to induce endothelial dysfunction in healthy adult subjects and type 2 diabetes mellitus patients (29).

In our study, the presence of systemic disease in patients with JIA was associated with increased carotid IMT when compared to patients with oligoarticular or polyarticular disease or healthy controls, suggesting a greater cardiovascular risk in this subgroup of patients. Increased carotid IMT, an established marker of cardiovascular prognosis in adult populations (4), has been demonstrated in adult CID patients (10–12) and in children/adolescents at high cardiovascular risk (7). Increased carotid IMT has been previously reported in patients with JIA compared to controls (15); IMT was greater in patients with polyarticular compared to oligoarticular disease (15), while patients with systemic JIA were not included in that study.

Increased IMT in patients with systemic compared to oligoarticular and polyarticular JIA observed in the present study was attributed to differences in age and other classic cardiovascular risk factors such as BMI, lipids, and blood pressure, as well as disease-related features such as disease activity and corticosteroids treatment. Disease activity has been related to an increased risk for subclinical atherosclerosis and cardiovascular events in adult CID patients (30). Corticosteroids treatment has also been associated with increased subclinical atherosclerosis in adults with CID (31). It is difficult to distinguish whether the corticosteroids treatment per se or the underlying disease that necessitates administration of corticosteroids is the main determinant of increased risk for premature atherosclerosis (1). Use of corticosteroids in our patients with JIA was related to differences in BMI, lipids, and blood pressure among patients with various disease types, in accordance with previous reports (1). This effect may have a further independent contribution on IMT. Larger studies are needed to investigate the relationship between disease activity and IMT progression in patients with JIA.

No differences in arterial stiffness or compliance were observed between patients with JIA and controls in our study. In contrast to our results, aortic PWV assessed by magnetic resonance imaging has been reported to be increased in patients with JIA (16). These findings probably reflect differences in methods used to assess aortic PWV in various studies. Increased PWV, a marker of adverse cardiovascular prognosis in various adult populations (5), has been demonstrated in adult CID patients (11, 32) and children at high cardiovascular risk (7, 33). LAEI and SAEI are relatively novel markers of arterial compliance that have been associated with cardiovascular risk factors (34, 35) and CID in adults (36), but their value in cardiovascular prognosis is not known. No previous studies assessed LAEI and SAEI in patients with JIA.

Our findings indicate a specific pattern of vascular dysfunction in children/adolescents with JIA. While endothelial function was impaired in patients with JIA, arterial stiffness indices did not differ between patients with JIA and healthy controls, and IMT was increased only in patients with systemic JIA. Similar findings have been previously reported in children with type 1 diabetes mellitus; endothelial dysfunction was reported in the absence of structural atherosclerotic changes (37). Previous studies in various populations have shown that endothelial dysfunction is detected long before the angiographic appearance of atherosclerosis on the vessel wall (22) and has been reported to predict the progression of carotid IMT (38). It could be speculated that JIA may be primarily associated with endothelial dysfunction, apparent even at ages 7–10 years, independently of the presence of systemic or nonsystemic disease. On the other hand, structural atherosclerotic changes could appear early only in the presence of systemic JIA, probably in association with the presence of active disease and use of corticosteroids.

Our study has some limitations. This was a cross-sectional observational study that could not investigate the causal nature of the associations observed. Although our study was powered to detect the prespecified level of differences in vascular indices between JIA patients and controls, it was underpowered to assess changes in vascular parameters among subgroups of JIA patients. Furthermore, patients with JIA were taking various medications that have been previously shown to affect vascular function in adults with CID (1), and this could have influenced the results of vascular studies. Although administration of specific medications was not related to vascular function indices in our study, the small number of patients in various subgroups of treatment did not provide the power needed for certain conclusions. More detailed measures of disease activity and severity should be assessed in relation to indices of vascular function in future studies.

In conclusion, children and adolescents with JIA demonstrate endothelial dysfunction compared to healthy controls, indicating an increased cardiovascular risk even at a very young age and independently of the type of disease. Impaired endothelial function in young patients with JIA was attributed to the inflammation that is an inherent feature of the disease. An increase in IMT was also found in young patients with systemic JIA compared to patients with oligoarticular/polyarticular disease or controls, potentially indicating a higher cardiovascular risk in this subgroup of patients. Arterial stiffness indices were not impaired in patients with JIA. Further studies are needed to investigate the development and progress of atherosclerosis in these young patients and evaluate the clinical and prognostic significance of our findings in patients with JIA.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Vlahos had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Vlahos, Naka, Alfantaki, Michalis, Siamopoulou.

Acquisition of data. Vlahos, Theocharis, Bechlioulis, Vakalis, Papamichael, Alfantaki, Gartzonika, Mavridis.

Analysis and interpretation of data. Vlahos, Theocharis, Bechlioulis, Naka, Papamichael, Michalis, Siamopoulou.

ROLE OF THE STUDY SPONSOR

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES

Procter & Gamble, Greece provided an educational grant for the study. They did not interfere with study design, results, or discussion. The publication of this article was not contingent on the approval of Procter & Gamble, Greece.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. REFERENCES
  • 1
    Pieringer H, Pichler M. Cardiovascular morbidity and mortality in patients with rheumatoid arthritis: vascular alterations and possible clinical implications. QJM 2011; 104: 1326.
  • 2
    Montecucco F, Mach F. Common inflammatory mediators orchestrate pathophysiological processes in rheumatoid arthritis and atherosclerosis. Rheumatology (Oxford) 2009; 48: 1122.
  • 3
    Kavey RE, Allada V, Daniels SR, Hayman LL, McCrindle BW, Newburger JW, et al. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research. Endorsed by the American Academy of Pediatrics. Circulation 2006; 114: 271038.
  • 4
    Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 2007; 115: 45967.
  • 5
    Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol 2010; 55: 131827.
  • 6
    Green DJ, Jones H, Thijssen D, Cable NT, Atkinson G. Flow-mediated dilation and cardiovascular event prediction: does nitric oxide matter? Hypertension 2011; 57: 3639.
  • 7
    Urbina EM, Williams RV, Alpert BS, Collins RT, Daniels SR, Hayman L, et al. Noninvasive assessment of subclinical atherosclerosis in children and adolescents: recommendations for standard assessment for clinical research: a scientific statement from the American Heart Association. Hypertension 2009; 54: 91950.
  • 8
    Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004; 31: 3902.
  • 9
    Lin YT, Wang CT, Gershwin ME, Chiang BL. The pathogenesis of oligoarticular/polyarticular vs systemic juvenile idiopathic arthritis. Autoimmun Rev 2011; 10: 4829.
  • 10
    Soltesz P, Der H, Kerekes G, Szodoray P, Szucs G, Danko K, et al. A comparative study of arterial stiffness, flow-mediated vasodilation of the brachial artery, and the thickness of the carotid artery intima-media in patients with systemic autoimmune diseases. Clin Rheumatol 2009; 28: 65562.
  • 11
    Stamatelopoulos KS, Kitas GD, Papamichael CM, Chryssohoou E, Kyrkou K, Georgiopoulos G, et al. Atherosclerosis in rheumatoid arthritis versus diabetes: a comparative study. Arterioscler Thromb Vasc Biol 2009; 29: 17028.
  • 12
    Gonzalez-Juanatey C, Llorca J, Martin J, Gonzalez-Gay MA. Carotid intima-media thickness predicts the development of cardiovascular events in patients with rheumatoid arthritis. Semin Arthritis Rheum 2009; 38: 36671.
  • 13
    Hansel S, Lassig G, Pistrosch F, Passauer J. Endothelial dysfunction in young patients with long-term rheumatoid arthritis and low disease activity. Atherosclerosis 2003; 170: 17780.
  • 14
    Sodergren A, Karp K, Boman K, Eriksson C, Lundstrom E, Smedby T, et al. Atherosclerosis in early rheumatoid arthritis: very early endothelial activation and rapid progression of intima media thickness. Arthritis Res Ther 2010; 12: R158.
  • 15
    Pietrewicz E, Urban M. Early atherosclerosis changes in children with juvenile idiopathic arthritis. Pol Merkur Lekarski 2007; 22: 2114. In Polish.
  • 16
    Argyropoulou MI, Kiortsis DN, Daskas N, Xydis V, Mavridis A, Efremidis SC, et al. Distensibility and pulse wave velocity of the thoracic aorta in patients with juvenile idiopathic arthritis: an MRI study. Clin Exp Rheumatol 2003; 21: 7947.
  • 17
    Chen CY, Tsao CH, Ou LS, Yang MH, Kuo ML, Huang JL. Comparison of soluble adhesion molecules in juvenile idiopathic arthritis between the active and remission stages. Ann Rheum Dis 2002; 61: 16770.
  • 18
    De Benedetti F, Vivarelli M, Pignatti P, Oliveri M, Massa M, Pistorio A, et al. Circulating levels of soluble E-selectin, P-selectin and intercellular adhesion molecule-1 in patients with juvenile idiopathic arthritis. J Rheumatol 2000; 27: 224650.
  • 19
    Ringold S, Wallace CA. Measuring clinical response and remission in juvenile idiopathic arthritis. Curr Opin Rheumatol 2007; 19: 4716.
  • 20
    Bechlioulis A, Kalantaridou SN, Naka KK, Chatzikyriakidou A, Calis KA, Makrigiannakis A, et al. Endothelial function, but not carotid intima-media thickness, is affected early in menopause and is associated with severity of hot flushes. J Clin Endocrinol Metab 2010; 95: 1199206.
  • 21
    Zimlichman R, Shargorodsky M, Boaz M, Duprez D, Rahn KH, Rizzoni D, et al. Determination of arterial compliance using blood pressure waveform analysis with the CR-2000 system: reliability, repeatability, and establishment of normal values for healthy European population: the seven European sites study (SESS). Am J Hypertens 2005; 18: 6571.
  • 22
    Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation 2004; 109 Suppl 1: III2732.
  • 23
    Deng YB, Li TL, Xiang HJ, Chang Q, Li CL. Impaired endothelial function in the brachial artery after Kawasaki disease and the effects of intravenous administration of vitamin C. Pediatr Infect Dis J 2003; 22: 349.
  • 24
    Nascif AK, Hilario MO, Terreri MT, Ajzen SA, D'Almeida V, Plavnik FL, et al. Endothelial function analysis and atherosclerotic risk factors in adolescents with systemic lupus erythematosus. Int J Adolesc Med Health 2007; 19: 497505.
  • 25
    Boros CA, Bradley TJ, Cheung MM, Bargman JM, Russell JL, McCrindle BW, et al. Early determinants of atherosclerosis in paediatric systemic lupus erythematosus. Clin Exp Rheumatol 2011; 29: 57581.
  • 26
    Wallberg-Jonsson S, Johansson H, Ohman ML, Rantapaa-Dahlqvist S. Extent of inflammation predicts cardiovascular disease and overall mortality in seropositive rheumatoid arthritis: a retrospective cohort study from disease onset. J Rheumatol 1999; 26: 256271.
  • 27
    Kerekes G, Szekanecz Z, Der H, Sandor Z, Lakos G, Muszbek L, et al. Endothelial dysfunction and atherosclerosis in rheumatoid arthritis: a multiparametric analysis using imaging techniques and laboratory markers of inflammation and autoimmunity. J Rheumatol 2008; 35: 398406.
  • 28
    Wallberg-Jonsson S, Ohman M, Rantapaa-Dahlqvist S. Which factors are related to the presence of atherosclerosis in rheumatoid arthritis? Scand J Rheumatol 2004; 33: 3739.
  • 29
    Ceriello A, Esposito K, Piconi L, Ihnat MA, Thorpe JE, Testa R, et al. Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients. Diabetes 2008; 57: 134954.
  • 30
    De Groot L, Posthumus MD, Kallenberg CG, Bijl M. Risk factors and early detection of atherosclerosis in rheumatoid arthritis. Eur J Clin Invest 2010; 40: 83542.
  • 31
    Del Rincon I, O'Leary DH, Haas RW, Escalante A. Effect of glucocorticoids on the arteries in rheumatoid arthritis. Arthritis Rheum 2004; 50: 381322.
  • 32
    Maki-Petaja KM, Hall FC, Booth AD, Wallace SM, Yasmin, Bearcroft PW, et al. Rheumatoid arthritis is associated with increased aortic pulse-wave velocity, which is reduced by anti-tumor necrosis factor-α therapy. Circulation 2006; 114: 118592.
  • 33
    Chow PC, Ho MH, Lee TL, Lau YL, Cheung YF. Relation of arterial stiffness to left ventricular structure and function in adolescents and young adults with pediatric-onset systemic lupus erythematosus. J Rheumatol 2007; 34: 134552.
  • 34
    Arnett DK, Glasser SP, McVeigh G, Prineas R, Finklestein S, Donahue R, et al. Blood pressure and arterial compliance in young adults: the Minnesota Children's Blood Pressure Study. Am J Hypertens 2001; 14: 2005.
  • 35
    Acree LS, Montgomery PS, Gardner AW. The influence of obesity on arterial compliance in adult men and women. Vasc Med 2007; 12: 1838.
  • 36
    Wright SA, O'Prey FM, Rea DJ, McHenry M, Johnston DG, McGivern RC, et al. Subclinical impairment of arterial mechanics in systemic lupus erythematosus identified by arterial waveform analysis. Rheumatol Int 2007; 27: 9618.
  • 37
    Babar GS, Zidan H, Widlansky ME, Das E, Hoffmann RG, Daoud M, et al. Impaired endothelial function in preadolescent children with type 1 diabetes. Diabetes Care 2011; 34: 6815.
  • 38
    Halcox JP, Donald AE, Ellins E, Witte DR, Shipley MJ, Brunner EJ, et al. Endothelial function predicts progression of carotid intima-media thickness. Circulation 2009; 119: 100512.