Table 3.

Investigations of structure and function of heart and / or arteries in children and adolescents with JIA with no clinical signs of cardiovascular dysfunction

Ref.	Design	No. of patients and controls	Age-group	Numbers of patients and subtypes	Number of patients in treatment at time of investigation	Study parameters	Significant findings
Stamato et al. 1995 [78]	Descriptive cross-sectional	36	10–17.5	36 HLA-B27 pos. with spondylarthropathy	No information	Echocardiographic assessment of left ventricle and the outflow tract.	Mild aortal regurgitation in patients unrelated to disease duration
	with an age matched healthy control group	33 *	6-18 *			Atrio-ventricular conduction
						Disease duration
Huppertz et al. 2000 [79]	Descriptive cross- sectional	40	6–26	35 HLA-B27 pos ERA	No information	Echocardiographic assessment of the left ventricle functions before and after exercise.	HLA-B27 positive ERA possibly at risk for development of aortic regurgitation and impaired myocardial relaxation
	with a control group of age and sexmatched HLA-B27 neg JIA and 25 healthy children	15 + 25 *	6 - 25 *	3 oligo		Atrio-ventricular conduction
				1 sJIA		BP
				1 unclassified
Oguz et al. 2000 [80]	Descriptive cross- sectional.	30	3–15	19 oligo	Mainly NSAID	Echocardiographic assessment of the left ventricle function	Higher systolic and diastolic BP, but within normal limits, and diastolic dysfunction of abnormal relaxation type in patients
	with an age matched healthy control group	30 *		10 poly	The patient with systemic JIA received corticosteroid	BP
				1 sJIA.	One unspecified patient received MTX
Argyropoulou et al. 2003 [81]	Descriptive cross-sectional	31	No data	18 oligo	No information	Evaluation by MR of aortic distensibility and PWV	Lower distensibility and higher PWV in patients unrelated to JIA subtype
	with an age matched healthy control group	28 *		6 poly		Disease activity	No correlations between aortic distensibility / PWV and metabolic and disease activity parameters
						Insulin sensitivity
						Lipid profile
				7 sJIA
Bharti et al. 2004 [82]	Descriptive cross-sectional.	35	No data	oligo	All received NSAID	Eccocardiographic evaluation of left ventricular function	Higher systolic and diastolic BP, but within normal rate, and higher resting heart rate in patients.
	with an age matched healthy control group	35 *		poly			Diastolic dysfunction and higher systolic and diastolic dimensions and volumes.
				sJIA
				No numbers given
Pietrewicz et al. 2007 [83]	Descriptive cross-sectional	40	4–16	32 oligo	No information	Echocardiographic assessment of cIMT	Increased cIMT in patients with JIA, highest in children with polyarthritis, and correlation between homocystein and cIMT
						Homocysteine
	with an age matched control group of healthy children	23 *	3–17 *	8 poly		CRP
						Lipid profile	Correlation between disease duration and cIMT
						Disease duration
Vlahos et al. 2011 [84]	Descriptive cross-sectional	30	7–18	15 oligo	3 NSAID	Echocardiographic assessment of cIMT	Reduced FMD in patients (as a group) associated with ESR but without any association to medication or clinical disease activity
	with a BMI, sex, and age matched control group of healthy children	33 *		8 poly	4 corticosteroid	PWV
						FMD
				7 sJIA	15 MTX	Arterial compliance	Increased cIMT in sJIA compared to controls or non-systemic JIA and related to use of corticosteroids, disease activity, BMI, blood pressure, dyslipidaemia, and age
					9 TNF-inhibitor	Disease activity
						BMI
						BP
						Glucose
						Lipid profile	No difference in PWV or arterial compliance between groups
						Smoking
Koca et al. 2012 [85]	Descriptive cross-sectional	50	5–16	22 oligo	No information	Echocardiographic assessment of left ventricle function	Impaired diastolic function in patients
				13 poly		Electrographic assessment
							No arrhythmias
				6 ERA
				4 PsA
				5 sJIA
	with a sex, and age matched control group of healthy children	70 *
	Follow-up after 12 month.
Abul et al. 2012 [86]	Descriptive cross-sectional	55	12.57 SD 2.9	24 oligo	22 NSAID	Echocardiographic assessment of right ventricular function	Systolic and diastolic dysfunction of the right ventricle
				8 poly	31 Salazopyrin
				15 ERA	31 MTX
	with a BMI, sex, and age matched control group of healthy children	33 *	11.9 SD 2.7 *	1 PsA	25 Corticosteroid	Disease activity	No association to medication including steroids and no associations to disease activity
				7 sJIA	2 TNF-inhibitor
Alkady et al. 2012 [66]	Descriptive cross- sectional	45	5–16	5 oligo	NSAID	Echocardiographic assessment of systolic and diastolic function (36 patients)	Higher resting heart rate and higher systolic and diastolic BP in patients but within normal range. Also enlarged left ventricular systolic dimensions and diastolic dysfunction. In 6 patients was found thickened pericardium, and in 9 mitral valve thickening and mild dysfunction.No association with disease activity reported.
				10 poly	26 MTX
				20 ERA	8 Corticosteroid
	with a sex and age matched control group of healthy children	30 *		1 PsA		Spirometry and CO diffusion (30 patients)
				9 sJIA
						23 patients and controls had both investigations
						Disease activity and duration
							In 19 out of 30 patients was found a reduction in pulmonary function primarily of a restrictive pattern, inversely correlated to disease duration and severity / treatment with MTX
Breda et al. 2012 and 2013 [33, 34]	Longitudinal intervention study of 12 months	38	4.7–9.4	Oligo- or poly	NSAID	cIMT	Improvement in all baseline disease parameters, including BT, after one year of “ treatment to target” except cHDL that was found normal at baseline and did not change. Positive correlation between cIMT and LDL and IL-1beta, no correlation to CRP or ESR. BT was found elevated at baseline but within normal range
				Mild disease in 22	MTX at baseline.	Clinical disease activity
						ESR, CRP
	with a sex, age and puberty stage matched control group of healthy children	40 *	4.1- 8.6*	Aggressive disease in 16 with poly	During follow-up disease control was obtained by 22 in treatment with NSAID +/- conventional DMARDs	Proinflammatory cytokines
						BP
						Lipid profile
						Oxidant status
					16 patients needed more aggressive treatment with TNF-alfa inhibition
Glowinska-Olszewska et al. 2013 [32]	Descriptive cross- sectional	58	11–15	28 oligo	42 Corticosteroid	BMI	22% of the patients met the criteria for overweight or obesity.
				26 poly	28 MTX	FMD
				4 sJIA	14 Biologics	cIMT
				Clin. active inflammation: 30	9 Unspec. DMARDS	LVMi	Lower FMD and higher cIMT, LVMi, BMI, and BP in patients as a group compared to controls; highest cIMT and lowest FMD in obese patients. No difference between patients with clinically active and inactive disease and no difference between JIA subtypes.
						Disease activity
						BP
						CRP
						IL-6, TNF-alfa
						Lipid profile
						Insulin sensitivity
	with a sex and age matched control group of healthy children with normal weight; no obese children	36 *	12-15 *	Clin. inactive inflammation: 28
Raab et al. 2013 [36]	Descriptive cross- sectional study of young adults with severe JIA, based on self-reports	344	19.7 SD 2.8	28 oligo	215 Biologics	Comorbidity	In 9.9% were reported CVD with hypertension in 7.3%, not different from the control group
				50 extended oligo
				91 RFneg poly
				37 RFpos poly	151 MTX	Disease activity
				75 ERA	64 Other conventional	Health	CVD, mainly hypertension, was reported in 40.6% of 15 patients with sJIA
				37 PsA	DMARDs	Functional deficits,
				15 sJIA
				11 other arthritis
	and compared to an age and sex matched cohort sampled from the general population	688 *
Aulie et al. 2014 [37]	Cross-sectional, observational study of patients with disease duration of more than 23 years	87	34.8–40.6	15 oligo	25 TNF-inhibitor	BP	Higher systolic and diastolic BT and small elevation of PWV in patients related to diastolic BT
				14 extended oligo	19 Methotrexate	PWV
				13 RF neg poly	23 Daily NSAID	AIx
				5 RF pos poly	6 Prednisolone	Coronary calcification
				18 ERA		Disease activity	No difference in AIx between patients and controls, but a positive association to diastolic BP, accumulated disease parameters inclusive treatment with prednisolone, and daily smoking, and a negative association to vigorous physical activity
				15 PsA
						CRP, ESR
						BMI and waist circumference
				4 sJIA		Lipid profile
				3 unclassified		Insulin resistance
						Self reported habits of smoking and physical activity
	With an age and sex matched group without DM or inflammatory arthritis selected from a national population register	87 *
							Coronary calcification was present in 26% of patients, a frequency not different from that found in a large population study, and related to waist circumference, BMI, systolic BP, blood glucose and years on daily prednisolone
Lianza et al. 2014 [77]	Two year prospective observational study	21	2.2–17.8	21 poly	TNF-inhibitor	Systolic and diastolic cardiac function evaluated by echocardiography	Mild ventricular diastolic dysfunction in JIA with no relation to NT-pro-BNP. Possible association between NT-pro-BNP and disease activity.
	with age and sex matched healthy controls	22 *	6 - 17 *			Cardiac biomarkers: NT-pro-BNP
						Troponin T	No sign of cardiovascular deterioration during treatment with TNF-alfa inhibitor.
						Disease activity
Satija et al. 2014 [71]	Cross sectional, observational	31	3.5–16	2 oligo	No DMARD or biologics	cIMT,	Reduced arterial elasticity in patients indicative of increased stiffness, all had normal BT. No difference in cIMT, FMD, GTN-MD between subgroups and controls
				2 RF neg poly		Arterial elasticity FMD
		31 *
						GTN-MD
						BT
				4 RF pos poly		Disease activity
				9 ERA		ESR
				14 sJIA		Lipid-profile	Correlation between cIMT and ESR
	With an age and sex matched control group of healthy children

SD is given in brackets. Aix Augmentation index, aIMT aorta intima-media thickness, BP blood pressure, CAC, coronary artery calcification, cIMT, carotis intima-media thickness, ERA Entesitis-related arthritis, ESR erythrocyte sedimentation rate, FMD flow mediated dilatation, GTN-MD glyceryl trinitrate mediated dilatation, LVMi left ventricle mass index, MTX Methotrexate, NSAID Non Steroid Anti-Inflammatory Drug, Oligo oligoarticular JIA, RF Rheuma-factor, Poly Polyarticular JIA, PsA Psoriasis associated JIA, sJIA systemic JIA, DMARD disease modifying anti-rheumatic drugs, PWV pulse wave velocity