Juvenile idiopathic arthritis burden on the cardiovascular system: A single centre experience

doi:10.21203/rs.3.rs-3876433/v1

Background

Adults with adolescent diagnosis of juvenile idiopathic arthritis (JIA), particularly those with the systemic phenotype, were found to have cardiovascular morbidities and earlier fatalities compared to the healthy controls.

Objective

to outline the possible early cardiovascular changes among patients with JIA.

Patients and Methods:

In this cross-sectional-controlled study with nested follow up, 57 JIA patients were enrolled and compared to age and sex matched 30 healthy subjects, at the period from September 2021 to September 2022. Patients with active JIA were followed up till remission. Assessment included echocardiography, tissue doppler to measure the carotid and aortic intima-media thickness (CIMT, AIMT), and the brachial artery flow mediated diameter (FMD), and serum endothelium (E)-selectin using ELISA technique.

Results

Serum levels of E-selectin were higher among JIA patients than in controls (p < 0.001), more increased during activity; whereas E-selectin level did not differ among categories of JIA. The estimated FMD, CIMT and AIMT did not show significant difference between patients and controls, however AIMT showed significant improvement with follow up of active patients and in patients treated with biological therapies. There was valvular affection and significant lower diameter of the left main coronary artery among patients with JIA compared to controls. There were no echocardiographic differences among the 3 categories of JIA, however, decrease in the mitral E/A and right ventricular myocardial performance index was found during follow up.

Conclusion

soluble E-selectin levels were higher among pediatric patients with JIA, particularly during activity denoting the possibility of early atherogenesis or subclinical cardiovascular disorder. Changes in AIMT during the follow up is another alarming sign. The reported changes were not related to the type of JIA rather than the activity status. Longitudinal cohorts are recommended for more precise evaluation of the cardiovascular burden of JIA.

Juvenile idiopathic arthritis

E-selectin

Flow mediated diameter

Echocardiography

Carotid intima-media thickness

Aortic intima-media thickness

Juvenile idiopathic arthritis (JIA) is the most common inflammatory rheumatic disease in children before the age of 16 years [1]. Increased cardiovascular risk and impaired indices of sub-clinical atherosclerosis were reported in adult populations with JIA [2]. The autoimmune and inflammatory mechanisms of the disease eventually lead to endothelial dysfunction and atherosclerosis [3]. About 50% of JIA patients still have an active disease when they reach adulthood [1].

Systemic JIA (SJIA) was the only studied subtype in pediatric age group regarding the presence of cardiovascular disorders (CVD). Pericarditis was reported in 30–35% of the patients even without apparent clinical signs. Endocarditis with thickened mitral valve and regurgitation was reported in 24.3% of the patients. Aortic valve thickening was reported in 5.4% of the patients. In addition, impaired diastolic function even in absence of any relevant cardiac symptoms and coronary artery dilatation were reported [4]. One autopsy study had suggested that 30% of children with JIA had evidence of atherosclerosis [5, 6].

Endothelial dysfunction is the first step in atherosclerosis and atherothrombosis, therefore, early detection of endothelitis may work as an early predictor for subclinical and overt CVD, and as a therapeutic target in patients at risk [7]. Evaluation of endothelial function and structural changes in the arterial wall can be made through measuring the serum level of endothelium (E)-selectin, the flow mediated diameter and the intima-media thickness. Therefore, this study traced the cardiovascular changes in pediatric patients with JIA through radiological and laboratory approaches, including a new technique for the pediatric age group.

Study settings: This cross-sectional-controlled study with nested follow up was conducted on 57 pediatric patients diagnosed as juvenile idiopathic arthritis (JIA) according to the American College of Rheumatology (ACR) and The International League of Associations for Rheumatology (ILAR) criteria of diagnosis [8, 9] from September 2021 to September 2022, and the end point of the cohort part was in March 2023. Patients were recruited from Pediatric Allergy, Immunology and Rheumatology Clinic, Children’s Hospital, Ain Shams University. Patients were compared to 30 age- and gender-matched healthy individuals.

Ethical considerations: The study gained approval of the Research Ethics Committee of the Department of Pediatrics, Faculty of Medicine, Ain Shams University. Ethical approval number is FMASU M D 182/2021 in accordance with the Declaration of Helsinki. Verbal consent was obtained from the guardians of all the enrolled individuals.

Inclusion criteria:

Diagnosis of JIA for at least 6 months duration
Age of the patients at time of enrollment was below 18 years old, and at time of diagnosis was below 16 years old
Both genders were included

Exclusion Criteria:

Patients with associated congenital heart diseases, primary immunodeficiency diseases, allergic diseases or other autoimmune disorders
Concurrent macrophage activation syndrome
Mixed connective tissue disease and overlap syndrome
Obesity or family history of hyperlipidemia
Hyperglycemia and diabetes mellitus

Sample size and method: The sample size was calculated using pass 11 program for sample size calculation, setting power at 90% and α-error at 0.05 and according to Hussain et al., 2021 [10]. Patients were recruited consecutively, and healthy control were enrolled subject to subject.

Study population: patients with JIA were classified into 3 categories: systemic JIA (SJIA), oligoarticular JIA (oligo-JIA) and polyarticular JIA (poly-JIA). Patients presented with disease activity were selectively followed up till complete remission. Activity and remission status of the disease was determined at time of enrollment according to juvenile arthritis disease activity score (JADAS) 10 [11, 12].

Study tools: All the included patients were subjected to:

Clinical history taking: including age, gender, duration of the disease, category of the disease, nature of the activity, systemic or articular, number of the involved joints, therapeutic agents used.
Anthropometric measurements: weight, height and body mass index (BMI)
Clinical examination: including arterial blood pressure measuring, other vital signs, presence of enlarged lymph nodes, liver or spleen, presence of any cardiac signs such as signs suggestive of venous or pulmonary congestion, signs of low cardiac output or thromboembolic manifestations. Articular examination was done according to Pediatric Gait, Arm, Leg and Spine (pGALS) technique [13], followed by precise assessment of the affected joint(s) as regards the presence of swelling, tenderness, hotness, redness, affected range of movement (ROM) and deformities.
Medical records were revised for any previous CVD, the positivity of antinuclear antibody (ANA) or rheumatoid factor (RF) titers, results of c-reactive protein (CRP), erythrocyte sedimentation rate (ESR), complete blood count (CBC) and lipid profile; and type of treatment either biological or non-biological disease modifying anti-rheumatic drugs (DMARDs).
Laboratory investigations: Both patients and controls were subjected to assessment of their serum levels of troponin I using anility ci series Abbott co. by chemiluminescence technique, and soluble E-selectin using commercially available enzyme-linked immunosorbent assay (ELISA) kits (Sun med biotechnology company) according to the manufacturer’s instructions.

E-Selectin was added to monoclonal antibody enzyme well which is pre-coated with E-Selectin monoclonal antibody, followed by incubation. E-Selectin antibodies were then labeled with biotin and combined with Streptavidin-HRP to form immune complex; then washed to remove the uncombined enzyme. Chromogen solution A 50μl, followed by chromogen solution B 50μl were added to each well, gently mixed, incubated for 10 min at 37℃ away from light. Stop Solution 50μl was added into each well to stop the reaction, and the blue mixture changed into yellow immediately. The chroma of color and the concentration of E-Selectin were positively correlated. The optical density (OD) under 450 nm wavelength was measured, then the standard curve linear regression equation was calculated.

6. Radiological investigations: conducted to all subjects and included:

Standard and continuous wave doppler echocardiography: to evaluate any pericardial, myocardial, endocardial or coronary artery affection. M-mode, two-dimensional and pulsed Doppler modalities were used. Images were obtained by a Hewlett-Packard Sonos 4500 echocardiogram with a 4.0-MHz transducer. The parameters were measured according to the American society of cardiology (ASC) recommendations [14], included: left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD), fractional shortening (FS), myocardial performance index (MPI) and valvular function.
Tissue doppler: it was performed on the brachial artery to measure FMD and common carotid artery (CCA) diameter for early detection of atherogenesis related changes in peripheral blood vessels. A standardized protocol of the Edimburgh Artery Study was used to assess the aortic intima-media thickness (AIMT) and carotid intima-media thickness (CIMT) by high resolution B-mode ultrasonography [15]. CIMT was measured at the distal wall of the carotid artery on a 10-mm segment and defined as the distance from the leading edge of the lumen-intima surface to the leading edge of the media–adventitia interface of the far wall [16]. For AIMT measurements, the most distal 15 mm of the abdominal aorta was scanned with a linear array transducer of a scanning frequency ranging from 7.5 to 13 MHz. The far wall of the distal abdominal aorta near the aortic bifurcation was therefore scanned, and image quality was optimized with gain settings and using the zoom function of the equipment. AIMT was measured proximal to the bifurcation at the midpoint between the renal arteries and the aortic bifurcation [15]. This was the first study to use this technique in the pediatric age group.
Arterial endothelial function was measured by evaluating brachial artery responses to endothelium-dependent stimuli (i.e., FMD) using an ultrasound scan. Brachial artery diameter was measured on B-mode ultrasound images, with a 7.5- to 10- MHz transducer and a high-resolution ultrasound machine (Samsung logiq P9 HS40). The right brachial artery was scanned in longitudinal section 2–8 cm above the elbow. Arterial diameters were measured at rest and during reactive hyperemia, which was induced by inflating a pneumatic cuff on the upper arm to supra-systolic pressure, then deflating the cuff after 4.5 minutes. Brachial artery diameter was scanned and recorded after deflation. End-diastolic arterial diameter was measured from one media–adventitia interface to the other at the clearest section three times, at baseline and every 2 minutes after reactive hyperemia. The maximum vessel diameter was defined as the average of the three consecutive maximum diameters measurements after hyperemia [16]. Vasodilation by reactive hyperemia was expressed as percent change in diameter compared with baseline values (FMD %). FMD was expressed as percent increase compared to basal vessel diameter (BVD) and calculated as; FMD = [(EDVR-BVD)/BVD] × 100.

Statistical Analysis: Data were collected, revised, coded and entered to the statistical package for social science (IBM SPSS) version 23. The quantitative data were presented as mean, standard deviations and ranges. Categorical variables were presented as number and percentages. The suitable corresponding tests for comparison and correlation were used. Receiver-operating characteristic (ROC) curve was used to examine the discriminative value of urinary or serum CC16. The area under the ROC curve (AUC) was interpreted as follows: AUC < 0.6 = fail, 0.6 to 0.69 = poor, 0.7 to 0.79 = fair, 0.8 to 0.89 = good, ≥ 0.9 = excellent. P value < 0.05 was considered significant.

Fifty-seven pediatric patients diagnosed as juvenile idiopathic arthritis (JIA), aged 6 to 16 years old, were included, involving 26/57 (45.6%) males and 31/57 (54.4%) females. None of the patients had family or personal history of cardiovascular diseases (CVD) and four patients had family history of rheumatological diseases. Anthropometric measurements of the patients revealed that 8.7% (5/57) had short stature, 12.3% (8/87) were obese with BMI ≥95^th percentile and 4/57 (7%) had BMI ≤ 5^thpercentile (Table 1). Two patients had systolic hypertension, one of them had SJIA and the other one had poly-JIA.

Patients were classified as follows: SJIA in 56.1% (32/57, oligo-JIA in 22.8% (13/57) and poly-JIA in 21.1% (12/57). At enrollment, 32/57 (56.1%) patients had active JIA with mean JADAS-10 19.9 ± 16.3, and the other 25/57 (43.9%) patients were in remission. Quotidian fever, evanescent rash and hepatosplenomegaly were found among 90.6% (29/32) SJIA patients and deformed joints were present in 10/57 (10.5%) patients (Table 2). As regards therapeutic modalities during the study duration, corticosteroids were administered to 16/25 patients, methotrexate (MTX) was administered to 50/57 patients (87.7%), and leflunomide was given to 10.5% (6/57) patients, as non-biological DMARDs. Biological DMARDs were needed for 30/57 patients, mainly anti-tumour necrosis factor (TNF) antibodies followed by tocilizumab (Table 3). Basic laboratory investigations revealed normal parameters of CBC and lipid profile and undetectable troponin-I. RF was elevated among 6/57 (10.5%) patients (2 in each category of JIA); and ANA was elevated in 12.3% (7/57) patients (3 with SJIA, 2 with oligo-JIA, and 2 with poly-JIA).

Serum levels of E-selectin showed higher estimates among JIA patients at time of enrollment than in the healthy control group (p <0.001) (table 4). Although no statistically significant differences were found, E-selectin levels were more elevated in patients with active JIA than in those in remission (Table 5). E-selectin levels were comparable among the 3 categories of JIA (Table 6). The predictive value of serum E-selectin using ROC curve revealed that levels higher than 342.2 ng/ml could discriminate JIA activity from healthy controls with a sensitivity of 96.9 % and specificity of 93.3 %. E-selectin level >275.1 ng/ml could discriminate JIA remission from healthy controls with a sensitivity of 96.0 % and specificity of 90.0% (Table 7).

The estimated values of basal and stimulated FMD, CIMT and AIMT did not show significant difference between patients and controls (Table 4), however, AIMT showed unexplained significantly higher measures in inactive JIA patients compared to active patients and controls (Table 5). Follow up of active JIA patients was associated with significant change in percentage of FMD change in 5 minutes and significant decrease in AIMT (Table 6).

As regards echocardiographic findings, valvular affection was more elicited among patients with JIA compared to healthy control. Additionally, there was significant decrease in the diameter of the left main coronary artery (LMCA) in the patients compared to the healthy control (Table 4). Although there were no significant differences among the 3 categories of JIA (Table 5), follow up of the active patients in their remittent status showed decrease in the mitral E/A and right ventricular myocardial performance index (RVMPI) (Table 6).

Some significant differences were observed in relation to the type of treatment. In patients with active JIA, treatment with biological DMARDs was associated with significantly lower estimates of AIMT (Table 8). During follow up evaluation, patients on biological DMARDs had better estimates of FMD in the brachial artery and LV MPI (Table 9).

Notably, correlations among the studied parameters were very limited. Soluble E-selectin level in active JIA patients were not correlated to the blood pressure measures or the basal or proportionate FMD. However, it was positively correlated with right ventricular systolic pressure (RVSP) and LMCA in echocardiography. On the other side, FMD was not correlated with any of the echocardiographic parameters.

In the current study, essential clinical and laboratory risk factors of cardiovascular disorders (CVD) were very limited. Systolic hypertension was limited to 2 patients, obesity was found among 12.3% of the patients, all of them were glucocorticoid- induced and none of them had hyperlipidemia. Therefore, we can claim that the elicited findings in this study would essentially relate to the disease pathogenesis or the therapeutic modality used. Notably, soluble E-selectin levels were significantly elevated in JIA patients compared to healthy control, and in active status compared to the remission status with significant diagnostic cutoff value in both situations. E-selectin, among other adhesive molecules, was reported in association with unstable angina and subendocardial infarctions, therefore, the elevated levels of soluble E-selectin in patients with JIA might augment the risk of CVD and atherogenesis [17]. E-selectin levels were reported in higher levels among patients with JIA than healthy control in Chen et al.’s study (2002) [18], and among patients with JIA activity compared to their peers in remission in Al-Haggar et al.’s study (2006) [19]. This might be attributed to the chronic inflammatory condition and the prolonged release of proinflammatory cytokines. However, elevation of the endothelial cell secreted E-selectin in response to an autoimmune disease affecting mainly the synovial membranes with or without systemic manifestations should deviate our thinking towards the possible CVD risk among patients with JIA, and the increased risk with the recurrent or uncontrolled disease activity, particularly that levels of E-selectin have declined significantly during follow up of the active patients at remission time. In this subject, we can conclude that E-selectin is more sensitive to endothelial changes in JIA than troponin-I, although the latter is widely used in practice.

Although the serum levels of E-selectin were more elevated among patients with SJIA than patients with oligo- and poly-JIA, the differences were not statistically significant, referring to the equal burden of the non-systemic forms of JIA on the cardiovascular system. Similarly, in other studies, soluble E-selectin was detected in higher levels in patients with SJIA than in those with oligo- and poly-JIA [18–20]. Furthermore, some authors found positive correlation between synovial and serum E-selectin levels in patients with JIA, particularly those with SJIA, claiming that serum E-selectin may work as a marker of severity or aggressiveness [21, 22].

Normal estimates of basal and stimulated flow mediated diameter (FMD) among the studied patients can be attributed to the normal lipid profile as an important modifier of FMD [23]. However, the lower estimate of the 5 min stimulated FMD in patients with active JIA should alert the thinking about the possible impact of the chronic inflammation alone on the atherogenesis risk [24]. Notably, significant increase in the percentage of FMD change was related to oligo-JIA followed by SJIA, reflecting possible endothelial dysfunction in patients with oligo-JIA despite absence of systemic manifestations. There was no significant impact of the modality of treatment, biological or non-biological on the basal or proportionate FMD during JIA activity.

Carotid intima media thickness (CIMT), another major vascular parameter, did not differ between patients and controls, between active and inactive disease, and among the 3 categories of JIA. Treatment modalities were not correlated to CIMT as well. Revising the different results in Vlahos et al (2011), whereas CIMT was the highest in patients with SJIA, followed by poly-JIA and least among patients with oligo-JIA, when they managed the other modifiable risk factors such as hypertension, dyslipidemia and the cumulative dose of glucocorticoids, the difference in CIMT estimates was lost [2]. Being an established marker of cardiovascular prognosis in adults [25], and in adult chronic inflammatory diseases [26] and in children/adolescents at high cardiovascular risk [27], concerns should be directed towards this parameter in patients with JIA, particularly that it was significantly affected during active JIA in other studies [10, 28].

Aortic intima media thickness (AIMT), measured for the first time in pediatrics, showed significantly higher estimates in JIA patients during remission, compared with active JIA and healthy control. However, it has significantly improved during following up patients with active JIA, and it was the sole parameter affected by the type of therapy. Increased AIMT remains a major risk for future CVD and should be considered as a practical tool to assess possible cardiovascular risk [5, 29].

Although all enrolled patients did not experience cardiac symptoms or signs, echocardiographic assessment revealed pericardial thickening in 2 patients and valvular affection in 11 patients, mainly mitral regurgitation (8/11). Asymptomatic echocardiographic findings should be dealt with cautiously. Similarly, in Al-Kady et al.’s (2012), 16.2% of the patients with JIA had asymptomatic pericardial effusion and 24.3% of them had mild mitral regurgitation [30]. However, functional echocardiography showed comparable functions between JIA patients and controls except for significant diametric narrowing of the left main coronary artery (LMCA), increased left ventricular end systolic dimension (LVESD), left ventricular end systolic volume (LVESV), left ventricular end diastolic dimension (LVEDD) and left ventricular end diastolic volume (LVEDV) in the patients’ group. Although Oguz et al (2000) agreed with the absence of functional changes among JIA patients [31], Bharti et al (2004) found significantly reduced EF and larger left ventricular systolic and diastolic dimensions, particularly in hypertensive patients with prolonged disease duration [32]. In Al-Kady et al. (2012), diastolic dysfunction was detected as well [30]. In accordance to our findings, Mody et al (1987) reported increased LVEDD values among patients with JIA [33], Corrao et al (1996) reported increased interventricular septum (IVS) thickness and left ventricular measurements [34], and Marin-Garcia et al (1984) also reported decreased contractility in two patients with JIA with abnormalities in the left ventricular diastolic function [35].

It was alarming to find out that abnormalities in echocardiographic findings in patients with active JIA did not disappear by time of disease remission, nether the pericarditis or the valvular affection, denoting that the systemic inflammatory process was still active despite disease remission by definition. Therefore, close monitoring of the fine changes in the echocardiography, FMD, CIMT and e-selectin would be required for patients with active JIA before declaring being in remission. Moreover, risk for CVD is better to be elucidated in every patient with JIA regardless of the associated systemic manifestations. Functional echocardiography showed significant improvement in the parameters of the diastolic function by time of remission, including the mitral E/A and MPI.

Interestingly, patients with active oligo-JIA had unique echocardiographic changes compared with patients with SJIA and poly-JIA, such as significant increase in mitral E/A ratio, indicating less risk of diastolic dysfunction, increased left sided MPI, which is associated with high risk of systolic dysfunction. Despite the non-significant difference, FS was higher among patients with active SJIA than those with active poly- and oligo-JIA. At time of disease remission, the three types of JIA were comparable as regards the echocardiographic findings. In another study, diastolic dysfunction was more evident among patients with active poly-JIA [32]. There is rarity of publications about echocardiographic findings in pediatric patients with JIA, in contrast to studies on adults.

Active JIA patients treated with biological therapies had lower estimates of AIMT, whereas patients in remission showed better estimates of left MPI than those who were treated with non-biological disease modifying anti-rheumatoid drugs (DMARDs). E-selectin levels were insignificantly higher among patients treated with biological agents. The cardio-protective effect of TNF inhibitors was illustrated by many authors. Bloom et al (2005) found that E-selectin was up-regulated among 3 patients with SJIA treated with TNF inhibitors, particularly, etanercept [22]. CIMT was reduced in patients treated with TNF inhibitors [36]. Data from the British Society for Rheumatology Biologics Register demonstrated up to a 60% reduction in myocardial infarction among patients who respond to anti-TNF within the first 6 months of treatment [37]. In a study conducted on 10156 patients, significantly fewer cardiovascular events occurred in patients treated with anti-TNF therapy [38]. Breda et al (2013) reported the potential effect of anti-TNF therapy, mainly etanercept, on cardiovascular indices in children with JIA, specifically on CIMT estimates [28]. This cardioprotective impact of anti-TNF agents might be attributed to the better control of the disease activity, with reduced frequency of flare ups, in addition to the elimination of the risk of GC in those patients, with further better control of the weight, blood pressure and lipid profile.

Juvenile idiopathic arthritis (JIA) is associated with asymptomatic significant elevation of E-selectin, changes in flow mediated diameter, increased carotid intimal thickness and echocardiographic changes, particularly during disease activity. Both systemic and oligoarticular JIA were associated with changes in the cardiovascular parameters. Treatment with biological agents could be cardioprotective.

Conflict of interest: Authors declare that they have no conflict of interest.

Funding: This work did not receive funding from any institute or company.

Author Contribution

All authors revised the final manuscript except the late G.M.G.M., G.S. and O.A. designed the research, collected data and followed up enrollment of patientsM.A. replaced G.M. in the middle of the research process after the death of the latter. M.A. followed up the cohort part of the research, revised and interpreted the results and shared in writing the final manuscript.G.S and O.A. collected the samples, analyzed the data and interpreted the results.G.S. wrote the final manuscript and corrected it after the revision of the other co-authors.A.A. (1) was responsible for the radiological investigations for all the participants in the form of brachial artery duplex to measure the basal and stimulated flow mediated diameter initially and at follow up. She shared in the methodology and data interpretation. A.A. (2) was responsible for analyzing the blood samples and doing the laboratory investigations. She shared in the methodology and data interpretation.E.E. was the pediatric cardiologist who was responsible for clinical and radiological assessment of the participants using echocardiography, measuring the carotid and aortic intima-media thickness. She shared in the methodology and data interpretation.

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Greenberg JD, Kremer JM, Curtis JR, Hochberg MC, Reed G, Tsao P, et al. Tumor necrosis factor antagonist use and associated risk reduction of cardiovascular events among patients with rheumatoid arthritis. Ann Rheum Dis. 2011; 70(4):576–82.

Table (1): Demographic and anthropometric data of the studied population

		Control group	JIA patients	Test of significance
		Mean ± SD N (%)	Mean ± SD N (%)	Value	p-Value
Age (Year)		9.7 ± 2.72	9.56 ± 3.62	t= 0.201	0.841
Gender	Male	18 (60%)	26 (45.61%)	X²= 1.627	0.202
Gender	Female	12 (40%)	31 (54.39%)	X²= 1.627	0.202
Weight KG		30.3 ± 7.18	34.39 ± 14.42	t= -1.764	0.081
Weight	decreased	0 (0%)	1 (1.75%)	FE	0.699
	Normal	30 (100%)	54 (94.74%)
	increased	0 (0%)	2 (3.51%)
Height		133.47 ± 16.18	130.16 ± 22.24	t= 0.720	0.474
Height	decreased	3 (10%)	5 (8.77%)	FE	1.00
	normal	27 (90%)	52 (91.23%)
	increased	0 (0%)	0 (0%)
BMI		16.86 ± 1.57	19.51 ± 3.99	t= -4.407	<0.001
BMI	Normal	27 (90%)	46 (80.7%)	FE	0.424
	decreased	2 (6.67%)	4 (7.02%)
	increased	1 (3.33%)	7 (12.28%)

BMI: body mass index, CVD: cardiovascular disease *Student t-test of significance (t). *Chi-Square test of significance (X²). *Fisher’s Exact test of significance.

Table (2): Characteristics of the JIA among the studied population

		N / Mean	% / SD	Median (IQR)	Range
Type of JIA	Oligo	13	22.8%
	Poly	12	21.1%
	Systemic	32	56.1%
Constitutional symptoms	Negative	28	49.1%
Constitutional symptoms	Positive	29	50.9%
Deformity	Negative	51	89.5%
Deformity	Positive	6	10.5%
Activity score		19.93	16.30	25 (0 - 35)	(0 - 40)

IQR: interquartile range, JIA: juvenile idiopathic arthritis, SD: standard deviation.

Table (3): Therapeutic modalities of JIA during the study duration

		Number	%
Methotrexate	Negative	7	12.3%
Methotrexate	Positive	50	87.7%
Response	Uncontrolled	26	52%
Response	Controlled	24	48%
Leflunomide	No	51	89.5%
Leflunomide	Yes	6	10.5%
Response	Controlled	4	66.7%
Response	Not controlled	2	33.3%
Etanercept	Negative	42	73.7%
Etanercept	Positive	15	26.3%
Response	Controlled	10	66.7%
Response	Not controlled	5	33.3%
Adalimumab	Negative	53	93%
Adalimumab	Positive	4	7%
Response	Controlled	3	75%
Response	Not controlled	1	25%
Infliximab	Negative	54	94.7%
Infliximab	Positive	3	5.3%
Response	Controlled	1	33.3%
Response	Not controlled	2	66.7%
Tocilizumab	Negative	40	70.2%
Tocilizumab	Positive	17	29.8%
Response	Controlled	16	94.1%
Response	Not controlled	1	5.9%
Anakinra	Negative	55	96.8%
Anakinra	Positive	2	3.2%
Response	Controlled	2	100%

Table (4): E-selectin, flow mediated diameter (FMD) and echocardiographic findings among the JIA patients and the healthy control groups

		Controls (30)	JIA patients (57)	Test of significance
		Median (IQR) Mean ± SD	Median (IQR) Mean ± SD	Value	p-Value
E-selectin (ng/ML)		187.15 (130.6 - 263.1)	945.9 (565 - 1387)	z= -7.099	<0.001
FMD baseline		25.33 ± 4.29	25.6 ± 4.97	t= -0.246	0.806
FMD 1min		27.57 ± 4.75	27.33 ± 4.97	t= 0.211	0.833
3min		27.8 ± 4.14	27.75 ± 4.84	t= 0.044	0.965
5min		27.07 ± 4.81	27.6 ± 5.24	t= -0.461	0.646
FMD %		6.23 (5.12 - 14)	7.5 (3.12 - 15.8)	z= -0.031	0.975
Pericardial affection	No	30 (100%)	55 (96.5%)	FE	0.543
Pericardial affection	Yes	0 (0%)	2 (3.5%)	FE	0.543
LVEDD		3.6 ± 0.5	3.6 ± 0.6	t= 0.457	0.649
LVESD		2.4 ± 0.5	2.4 ± 0.5	t= -0.126	0.900
EF		68.9 ± 6.6	66.5 ± 5.5	t= 1.842	0.069
FS		34.9 ± 7.6	34.4 ± 5.1	t= 0.277	0.783
RVSP		28.6 ± 4.2	27.2 ± 3.4	t= 1.712	0.091
Mitral E/A		1.7 (1.3 - 2)	1.7 (1.3 - 2.3)	z= -0.698	0.485
Valvular affection	No	30 (100%)	46 (80.7%)	FE	0.014
Valvular affection	Yes	0 (0%)	11 (19.3%)	FE	0.014
RT MPI		0.5 (0.4 - 0.6)	0.5 (0.4 - 0.6)	z= -1.655	0.098
LT MPI		0.6 (0.4 - 0.7)	0.5 (0.5 - 0.7)	z= -0.219	0.827
LMCA		2 (1.5 - 2.2)	1.6 (1.4 - 2)	z= -2.094	0.036
RMCA		1.5 (1.2 - 1.8)	1.5 (1.3 - 1.6)	z= -0.697	0.486
CIMT		1.2 (1.1 - 1.3)	1.2 (1.1 - 1.3)	z= -0.364	0.716
AIMT		1.4 (1.2 - 1.7)	1.5 (1.4 - 1.8)	z= -1.544	0.123

FMD: flow mediated diameter. LVEDD: left ventricular end diastolic diameter, LVESD: left ventricular end systolic diameter, EF: ejection fraction, FS: fractional shortening, RVSP: right ventricular systolic pressure, MPI: myocardial performance index, LMCA: left main coronary artery, RMCA: right main coronary artery, CIMT: carotid intimal medial thickness, AIMT: aortic intimal medial thickness *Fisher’s Exact test of significance, *Mann-Whitney test of significance (z), *Student t-test of significance (t).

Table (5): E selectin level, FMD and echocardiographic findings among JIA patients in activity, in remission and the healthy control groups

	Healthy Control	Activity	Remission	Test of significance
	Mean ± SD Median (IQR)	Mean ± SD Median (IQR)	Mean ± SD Median (IQR)	Value	p-Value
E-selectin (ng/ML)	187.15 (130.6 – 263.1)	1093 (788.1 – 1669)	749.6 (418.2 – 977.6)	H= 53.598	<0.001(K1)
FMD baseline	25.33 ± 4.29	25.66 ± 5.29	25.52 ± 4.63	f= 0.036	0.965
FMD 1min	27.57 ± 4.75	27.47 ± 5.25	27.16 ± 4.68	f= 0.050	0.952
3min	27.8 ± 4.14	27.84 ± 5.22	27.64 ± 4.41	f= 0.014	0.986
5min	27.07 ± 4.81	27.41 ± 5.25	27.84 ± 5.31	f= 0.156	0.856
FMD %	6.23 (5.12 - 14)	7.35 (3 - 16.2)	8.3 (3.4 - 15.3)	H= 0.003	0.999
LVEDD	3.6 ± 0.5	3.5 ± 0.6	3.6 ± 0.6	f= 0.48	0.620
LVESD	2.4 ± 0.5	2.4 ± 0.5	2.5 ± 0.4	f= 0.28	0.759
EF	68.9 ± 6.6	66.3 ± 5.7	66.8 ± 5.2	f= 1.74	0.182
FS	34.9 ± 7.6	34.3 ± 5.6	34.6 ± 4.5	f= 0.06	0.938
RVSP	28.6 ± 4.2	27.3 ± 3.7	27.1 ± 2.9	f= 1.48	0.234
MITRAL E/A	1.7 (1.3 - 2)	1.7 (1.3 - 2.2)	1.7 (1.4 - 2.3)	H= 0.73	0.693
RT MPI	0.5 (0.4 - 0.6)	0.5 (0.4 - 0.6)	0.4 (0.3 - 0.5)	H= 5.22	0.074
LT MPI	0.6 (0.4 - 0.7)	0.5 (0.5 - 0.7)	0.6 (0.5 - 0.7)	H= 0.73	0.693
LMCA	2 (1.5 - 2.2)	1.8 (1.4 - 2)	1.6 (1.3 - 1.8)	H= 5.01	0.082
RMCA	1.5 (1.2 - 1.8)	1.4 (1.3 - 1.6)	1.5 (1.3 - 1.7)	H= 1.42	0.491
CIMT	1.2 (1.1 - 1.3)	1.2 (1.1 - 1.3)	1.2 (1 - 1.3)	H= 1.17	0.558
AIMT	1.4 (1.2 - 1.7)	1.4 (1.3 - 1.6)	1.5 (1.4 - 2)	H= 6.75	0.034^(K1)

FMD: flow mediated diameter. LVEDD: left ventricular end diastolic diameter, LVESD: left ventricular end systolic diameter, EF: ejection fraction, FS: fractional shortening, RVSP: right ventricular systolic pressure, MPI: myocardial performance index, LMCA: left main coronary artery, RMCA: right main coronary artery, CIMT: carotid intimal medial thickness, AIMT: aortic intimal medial thickness *One Way ANOVA test of significance (f). *Kruskal Wallis test of significance (H). Post hoc was significant between: (K1) Controls Vs (activity and remission groups).

Table (6): E-selectin level, FMD and echocardiographic findings among different types of JIA in the studied patients

	Type Of JIA			Test of significance
	Oligo	Poly	Systemic	Test of significance
	Mean ± SD Median (IQR)	Mean ± SD Median (IQR)	Mean ± SD Median (IQR)	Value	p-Value
E-selectin in activity (ng/ML)	830.4 (545.5 - 1141)	792.9 (531.7 - 1180.1)	995.5 (655.8 - 1408.5)	H= 0.58	0.747
E-selectin in follow up	421.8 (320 - 801.4)	501.35 (458.8 - 544.2)	458.1 (385.4 - 548.6)	H= 0.52	0.770
FMD baseline	29.2 ± 3.8	26.1 ± 5	23.9 ± 4.6	f= 6.34	0.003^(A1)
FMD 1min	30.9 ± 4.9	27.6 ± 4.4	25.8 ± 4.5	f= 5.53	0.007^(A1)
3min	31.3 ± 4.9	27.9 ± 4.5	26.3 ± 4.3	f= 5.96	0.005^(A1)
5min	31.1 ± 5	27.3 ± 5.2	26.3 ± 4.8	f= 4.36	0.018^(A1)
FMD %	6.6 (4.5 - 9.1)	7.75 (3.2 - 11.1)	10.5 (-0.7 - 21.5)	H= 0.89	0.640
FMD baseline in remission	25 ± 5	24.8 ± 7.4	24.3 ± 4.7	f= 0.02	0.977
FMD in remission 1MIN	28.7 ± 4	28 ± 6.2	25.8 ± 3.7	f= 0.68	0.521
3MIN	29 ± 4.6	29 ± 4.2	25.9 ± 4.8	f= 0.9	0.428
5MIN	26.7 ± 4	28 ± 6.1	23.9 ± 5.1	f= 1.01	0.388
FMD% in remission	9 (8.8 - 21)	11.35 (6.7 - 24)	3.9 (-5.3 - 7.5)	H= 4.67	0.097
LVEDD (Activity)	3.33 ± 0.74	3.78 ± 0.5	3.57 ± 0.56	f= 1.773	0.179
LVESD (Activity)	2.35 ± 0.55	2.42 ± 0.37	2.42 ± 0.47	f= 0.094	0.911
EF (Activity)	66.15 ± 4.36	67.88 ± 5.6	66.16 ± 5.89	f= 0.463	0.632
FS (Activity)	30.77 ± 3.37	36.42 ± 4.78	35.19 ± 5.16	f= 5.345	0.008^(A1)
RVSP (Activity)	26.23 ± 4.25	27.92 ± 3.5	27.34 ± 2.98	f= 0.820	0.446
MITRAL E/A (Activity)	2.25 (2 - 3)	1.6 (1.45 - 1.85)	1.55 (1.2 - 1.92)	H= 10.838	0.004^(K1)
RT MPI (Activity)	0.38 (0.34 - 0.58)	0.45 (0.3 - 0.56)	0.45 (0.38 - 0.56)	H= 1.530	0.465
LT MPI (Activity)	0.65 (0.52 - 0.86)	0.47 (0.39 - 0.58)	0.54 (0.45 - 0.7)	H= 7.117	0.028^(K2)
LMCA (Activity)	1.6 (1.3 - 1.8)	1.8 (1.2 - 1.95)	1.65 (1.4 - 2)	H= 0.719	0.698
RMCA (Activity)	1.7 (1.6 - 1.8)	1.55 (1.3 - 1.6)	1.4 (1.2 - 1.5)	H= 6.941	0.031^(K3)
CIMT (Activity)	1 (1 - 1.3)	1.2 (1.05 - 1.2)	1.2 (1.2 - 1.3)	H= 5.058	0.080
AIMT (Activity)	1.8 (1.5 - 2)	1.5 (1.4 - 2)	1.4 (1.3 - 1.5)	H= 4.915	0.086
LVEDD (remission)	3.13 ± 0.6	3.58 ± 0.43	3.49 ± 0.37	f= 1.052	0.375
LVESD (remission)	2.3 ± 0.26	2.23 ± 0.39	2.27 ± 0.35	f= 0.042	0.959
EJ (remission)	66.67 ± 4.04	67.5 ± 7.33	70 ± 7.5	f= 0.348	0.712
FS (remission)	30 ± 4	35 ± 6.78	37.3 ± 6.73	f= 1.503	0.256
RVSP (remission)	28.33 ± 7.64	28.75 ± 6.99	28.8 ± 3.08	f= 0.010	0.990
MITRAL E/A (remission)	1.5 (1.5 - 1.6)	1.65 (1.25 - 2)	1.2 (1.2 - 1.3)	H= 3.939	0.140
RT MPI (remission)	0.42 (0.34 - 0.43)	0.43 (0.32 - 0.5)	0.47 (0.41 - 0.51)	H= 1.859	0.395
LTMPI (remission)	0.56 (0.33 - 0.67)	0.53 (0.46 - 0.56)	0.66 (0.52 - 1)	H= 2.316	0.314
LMCA (remission)	1.4 (1.3 - 2)	1.6 (1.1 - 2)	1.4 (1 - 2)	H= 0.078	0.962
RMCA (remission)	1.3 (1.2 - 2)	1.75 (1.45 - 2)	1.6 (1.2 - 2)	H= 0.799	0.670
CIMT (remission)	1.2 (1.1 - 1.3)	1.15 (1.05 - 1.2)	1.2 (1.1 - 1.3)	H= 1.405	0.495
AIMT (remission)	1.2 (1.1 - 1.2)	1.3 (1.2 - 1.7)	1.3 (1.2 - 1.4)	H= 2.413	0.299

JIA: juvenile idiopathic arthritis. *One Way ANOVA test of significance (f). *Post-hoc Bonferroni test was significant between: (A1) Oligo Vs. Systemic group. *Kruskal Wallis test of significance (H).

Table (7): Predictive value of E-selectin for JIA activity and remission from healthy control

	AUC	95% CI	Sig.	Cut-off value	Sensitivity	Specificity	+PV	-PV
Activity	0.961	0.879 to 0.994	<0.001	>342.2	96.9	93.3	93.9	96.6
Remission	0.969	0.883 to 0.997	<0.001	>275.1	96.0	90.0	88.9	96.4

AUC: area under the curve

Table (8): E-selectin level, FMD and echocardiographic parameters in patients with JIA in activity according to the treatment modality

		DMARDs (27)	Biological treatment (30)	Test of significance
		Median (IQR) Mean ± SD	Median (IQR) Mean ± SD	Value	p-Value
E-selectin (ng/ML)		904.1 (531.4 - 1251)	983.45 (582.2 - 1430)	z= -0.711	0.477
FMD	FMD baseline	26 ± 5.66	25.23 ± 4.31	t= 0.578	0.565
	FMD 1min	27.48 ± 5.98	27.2 ± 3.95	t= 0.212	0.833
	3min	28.22 ± 5.89	27.33 ± 3.71	t= 0.689	0.493
	5min	28.22 ± 5.83	27.03 ± 4.66	t= 0.854	0.397
	FMD %	7.5 (3.12 - 16.6)	7.57 (0 - 15.8)	z= -0.128	0.898
Echo	LVEDD	3.55 ± 0.65	3.57 ± 0.56	t= -0.115	0.909
	LVESD	2.48 ± 0.41	2.34 ± 0.5	t= 1.153	0.254
	EF	66.58 ± 4.7	66.47 ± 6.17	t= 0.076	0.940
	FS	34.15 ± 4.11	34.7 ± 5.9	t= -0.405	0.687
	RVSP	26.41 ± 3.12	27.93 ± 3.52	t= -1.724	0.090
	Mitral E/A	1.7 (1.5 - 2.6)	1.7 (1.3 - 2.03)	z= -1.072	0.284
	RT MPI	0.43 (0.34 - 0.56)	0.46 (0.37 - 0.56)	z= -0.484	0.628
	LT MPI	0.56 (0.48 - 0.7)	0.52 (0.43 - 0.66)	z= -1.063	0.288
	LMCA	1.6 (1.2 - 2)	1.8 (1.4 - 2)	z= -1.173	0.241
	RMCA	1.5 (1.3 - 1.7)	1.4 (1.2 - 1.6)	z= -1.008	0.313
	CIMT	1.2 (1 - 1.3)	1.2 (1.2 - 1.3)	z= -1.895	0.058
	AIMT	1.5 (1.4 - 2)	1.4 (1.3 - 1.5)	z= -2.875	0.004

FMD: flow mediated dilatation, LVEDD: left ventricular end diastolic diameter, LVESD: left ventricular end systolic diameter, EF: ejection fraction, FS: fractional shortening, RVSP: right ventricular systolic pressure, MPI: myocardial performance index, LMCA: left main coronary artery, RMCA: right main coronary artery, CIMT: carotid intimal medial thickness, AIMT: aortic intimal medial thickness*Mann-Whitney test of significance (z). *Student t-test of significance (t).

Table (9): E-selectin level, FMD and echocardiographic parameters in patients with JIA after going through remission, according to the treatment modality

		DMARDs (27)	Biologics (30)	Test of significance
		Median (IQR) Mean ± SD	Median (IQR) Mean ± SD	Value	p-Value
E-selectin R ng/ml		397.95 (320 - 475.9)	477.4 (421.8 - 561.6)	z= -0.930	0.352
FMD	FMD R BASE	30 ± 0	23.8 ± 4.99	t= 1.709	0.108
	FMD R 1MIN	33 ± 0	26 ± 3.85	t= 7.034	<0.001
	3MIN	33.5 ± 0.71	26.33 ± 4.27	t= 2.305	0.036
	5MIN	31 ± 0	24.6 ± 5.05	t= 1.741	0.102
	FMD%	8.25 (7.7 - 8.8)	6.6 (-3.7 - 15)	z= -0.447	0.655
Echo	LVEDD	3.45 ± 0.35	3.45 ± 0.45	t= 0.010	0.992
	LVESD	2.25 ± 0.21	2.27 ± 0.35	t= -0.065	0.949
	EJ	64.5 ± 2.12	69.4 ± 7.01	t= -0.958	0.353
	FS	33.5 ± 0.71	35.73 ± 7.04	t= -0.436	0.669
	RVSP	24 ± 5.66	29.33 ± 4.37	t= -1.586	0.134
	Mitral E/A	1.35 (1.2 - 1.5)	1.3 (1.2 - 1.79)	z= -0.227	0.820
	RT MPI	0.36 (0.34 - 0.38)	0.45 (0.41 - 0.51)	z= -1.924	0.054
	LTMPI	0.37 (0.33 - 0.41)	0.61 (0.52 - 0.83)	z= -1.992	0.046
	LMCA	1.5 (1 - 2)	1.4 (1.2 - 2)	z= -0.303	0.762
	RMCA	2 (2 - 2)	1.5 (1.2 - 2)	z= -1.217	0.224
	CIMT	1.25 (1.2 - 1.3)	1.2 (1.1 - 1.2)	z= -1.092	0.275
	AIMT	1.2 (1.2 - 1.2)	1.3 (1.2 - 1.4)	z= -0.765	0.444

FMD: flow mediated dilatation, LVEDD: left ventricular end diastolic diameter, LVESD: left ventricular end systolic diameter, EF: ejection fraction, FS: fractional shortening, RVSP: right ventricular systolic pressure, MPI: myocardial performance index, LMCA: left main coronary artery, RMCA: right main coronary artery, CIMT: carotid intimal medial thickness, AIMT: aortic intimal medial thickness *Mann-Whitney test of significance (z). *Student t-test of significance (t).

No competing interests reported.

Juvenile idiopathic arthritis burden on the cardiovascular system: A single centre experience

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Abstract

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Results

Conclusion

Introduction

Patients and Methods

Results

Discussion

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