
==== Front
Rheumatology (Oxford)
Rheumatology (Oxford)
brheum
Rheumatology (Oxford, England)
1462-0324
1462-0332
Oxford University Press

37788103
10.1093/rheumatology/kead505
kead505
Clinical Science
AcademicSubjects/MED00360
The risk of cardiovascular comorbidity in children with Behçet’s disease
https://orcid.org/0000-0002-4320-8632
Demir Selcan Department of Pediatric Rheumatology, Eskisehir Osmangazi University Medical Faculty, Eskisehir, Turkey

https://orcid.org/0000-0002-4365-2995
Duzova Ali Department of Pediatric Nephrology, Hacettepe University Medical Faculty, Ankara, Turkey

Karagoz Tevfik Department of Pediatric Cardiology, Hacettepe University Medical Faculty, Ankara, Turkey

Oguz Berna Department of Pediatric Radiology, Hacettepe University Medical Faculty, Ankara, Turkey

https://orcid.org/0000-0001-5136-3977
Aykan Hayrettin Hakan Department of Pediatric Cardiology, Hacettepe University Medical Faculty, Ankara, Turkey

Satirer Ozlem Department of Pediatrics, Hacettepe University Medical Faculty, Ankara, Turkey

https://orcid.org/0000-0002-6542-2656
Sag Erdal Department of Pediatric Rheumatology, Hacettepe University Medical Faculty, Ankara, Turkey

Ozen Seza Department of Pediatric Rheumatology, Hacettepe University Medical Faculty, Ankara, Turkey

Bilginer Yelda Department of Pediatric Rheumatology, Hacettepe University Medical Faculty, Ankara, Turkey

Correspondence to: Yelda Bilginer, Division of Rheumatology, Department of Pediatrics, Hacettepe University Faculty of Medicine, No: 2, A. Adnan Saygun Street, Altındağ, Ankara 06100, Turkey. E-mail: yeldabilginer@yahoo.com
9 2024
03 10 2023
03 10 2023
63 SI2 Focusing on children and adolescents with rheumatic diseases SI188SI194
01 6 2023
09 9 2023
11 10 2023
© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.
2023
https://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objective

Patients with Behçet’s disease (BD) may experience long-term morbidity caused by various forms of cardiovascular disease. This study aimed to assess the risk for cardiovascular comorbidity in paediatric BD patients with and without vascular involvement, independent of the contribution of traditional risk factors.

Methods

Paediatric patients classified as having BD according to the 2015 Peadiatric BD (PEDBD) criteria were included in the study. Twenty-four-hour ambulatory blood pressure monitoring (ABPM), transthoracic echocardiography, and carotid intima-media thickness (cIMT) measurements were performed. Patients with an active disease or those who have other known risk factors for cardiovascular disease were not included in the study.

Results

Thirty-one children and adolescents with paediatric BD (16 female, 51.6%; F/M: 1.06) were enrolled in the study. Among the BD patients, 10 patients (34.4%) had abnormal ABPM. Carotid IMT values, mean arterial pressure, systolic and diastolic blood pressure by ABPM and the prevalence of abnormal ABPM, non-dipping, and ambulatory hypertension were similar between patients with and without vascular involvement. The echocardiography measurements showed that BD patients with vascular involvement had a significantly higher velocity and velocity time integral of the left ventricle outflow tract, which may indicate increased stiffness of the aorta.

Conclusion

Paediatric BD patients with vascular involvement may tend to have more cardiovascular risk factors. However, cardiovascular assessment should be considered in all BD patients, regardless of the involved systems. We suggest that ABPM may accurately define hypertension and cardiovascular risk in BD.

paediatric Behçet’s disease
cardiovascular comorbidity
premature atherosclerosis
hypertension
arterial stiffness
intima-media thickness
twenty-four-hour ambulatory blood pressure monitoring
ABPM
transthoracic echocardiography
==== Body
pmcRheumatology key messages Paediatric Behçet’s disease (BD) patients with vascular involvement may tend to have more cardiovascular risk factors.

BD patients should be evaluated for cardiovascular comorbidities, regardless of the involved systems.

ABPM may accurately identify hypertension and increased cardiovascular risk in BD.

Introduction

Behçet’s disease (BD) is a multigenic autoinflammatory disorder characterized by recurrent mucocutaneous, ocular, musculoskeletal, vascular, gastrointestinal and CNS manifestations [1]. Unlike other systemic vasculitis, BD can affect any type and size of blood vessels [2]. Although BD patients are diagnosed more frequently in the second or third decade of life, the first symptoms appear under the age of 16 years in 4–26% of patients [3]. Due to the rarity and heterogeneity of BD during childhood, the diagnosis and management are challenging.

The overall mortality rate of patients with BD is significantly higher among patients under 25 years of age and in the early disease course. Furthermore, vascular involvement is one of the major causes of morbidity and mortality and occurs in up to 40% of patients with BD [4].

Considering the increased inflammatory nature of BD compared with other forms of vasculitis, it is expected that recurrent inflammation attacks will affect the endothelium and contribute to the development of atherosclerosis chronically. Recent studies showed that increased carotid intima-media thickness (cIMT) was significantly associated with endothelial cell dysfunction (ECD), which is regarded as the early marker of atherogenesis [5, 6]. ECD has also been shown in patients with BD [7–10]. However, the contribution of accelerated and early atherosclerosis to cardiovascular comorbidity of BD needs to be clarified. Cardiac involvement in BD has been reported between 2.4 and 6.4% of patients and includes coronary artery disease, as well [4, 11, 12]. Cardiovascular disease affects mostly younger BD patients and is often manifested in the form of myocardial infarction or angina [13]. A prospective study on BD patients who had no history of cardiovascular disease reported that BD patients had intrinsic left ventricular dysfunction on speckle tracking echocardiography, despite having no apparent abnormality on routine echocardiography [14]. It is still under debate to what extent BD increases the cardiovascular disease risk, especially in individuals without other traditional risk factors such as obesity, metabolic syndrome, or smoking. The increased burden of cardiovascular comorbidity in SLE patients has already been well documented [15]; traditional atherosclerotic risk factors contribute to increased risk but cannot fully explain the accelerated cardiovascular disease in SLE [16]. This risk is even more pronounced among younger SLE patients [17].

In fact, vascular BD is mostly seen in younger patients, and it is not clear whether BD patients with vascular involvement are at greater risk for future cardiovascular disease. In this study, we aimed to evaluate the cardiovascular assessment of paediatric BD patients with and without vascular involvement. We evaluated 31 paediatric BD patients with 24-h ambulatory blood pressure monitoring (ABPM), transthoracic echocardiography, and cIMT to determine whether there is an increased risk of cardiovascular comorbidity in the paediatric population with vascular BD.

Patients and methods

Study population

Thirty-one BD patients who were followed at a paediatric rheumatology outpatient clinic between January 2017 and December 2019 were prospectively enrolled into the study. Patients (<16 years of age at disease onset and diagnosis) were classified as having BD according to the Pediatric Behçet’s Disease (PEDBD) classification criteria [18]. Patients with a history of arterial occlusions, and/or stenosis, and/or aneurysms and/or venous thrombosis formed the BD patient group with vascular involvement.

Current disease activity during the assessments was calculated for each patient using the BD activity form [19]. Patients with an active organ and/or system involvement (oral ulcer, genital ulcer, skin lesions, uveitis, retinal vasculitis, thrombophlebitis, arthritis, gastrointestinal involvement, neurologic involvement) and patients who had other known risk factors for cardiovascular disease [such as obesity (BMI > 30), hypertension, diabetes mellitus, or metabolic syndrome] were excluded.

When the patients came for routine visits, a physical examination and laboratory tests (complete blood count, serum creatinine, lipid profile, acute phase reactants, and urine test) were performed. During the same week, cIMT measurement, echocardiography and 24-h ABPM were also performed. Ethical approval was obtained from the Hacettepe University Faculty of Medicine Institutional Review Board. Written informed consent was obtained from the parents of all subjects involved in the study.

Twenty-four-hour ambulatory blood pressure monitoring

Twenty-four-hour ABPM was performed in 29 patients; Spacelabs ABPM devices (Model no: 90207–30) were used. Measurements were performed every 15–20 min during daytime (waking hours) and every 30 min during the night (sleep periods). The mean systolic BP (SBP), diastolic BP (DBP) and arterial pressure (MAP) levels and load (percentage of readings above the ambulatory 95th percentile by sex and age) were calculated for the 24-hour period. Daytime was defined as from 08.00 a.m. to 08.00 pm, and nighttime was defined as from midnight to 06.00 a.m. S.D. scores for SBP, DBP and MAP were determined according to the standard values adjusted by age and gender [20]. S.D. score indicates how many S.D.s an observation is above or below the mean/median: S.D. score = (observed value – mean/median value of the reference population)/(S.D. value of reference population). The presence of SBP or DBP or MAP being equal to or greater than the 95th percentile was defined as hypertension. Dipping was defined as the percentage decline in mean systolic or diastolic levels from daytime to nighttime [100 × (mean daytime – mean nighttime)/(mean daytime)]; non-dipping was defined as a dipping level of <10%.

Carotid intima-media thickness measurements

The intima-media thickness of a vessel is the distance from the lumen–intima interface to the media adventitia interface. US examination was performed to measure the cIMT of the right and left common carotid arteries. To avoid inter-observer variability, all cIMT measurements were performed by the same expert, who was unaware of the clinical characteristics of the patients. Patients were scanned in the supine position and with the neck rotated to the opposite side of examination by using an 8-MHz annular array US imaging system (Siemens Acuson P50 Ultrasound system, Siemens Medical Solution USA, Inc. Mountain View, California, USA). The cIMT was measured at 10 mm proximal to the distal end of the common carotid artery (CCA) in a straight segment (at least 10 mm long) from the far wall. Five measurements were obtained and recorded in millimetres (mm) for the right and left common carotid arteries, then the arithmetic mean was calculated for each side. cIMT S.D.s adjusted for age, height and sex were calculated using reference values [21].

Transthoracic echocardiographic assessments

All patients underwent standard M-mode, 2-dimensional and Doppler transthoracic echocardiographic assessments. Echocardiographic evaluations were performed using a GE Vivid E9 with XD clear or GE Vivid S5 (GE Healthcare, Horten, 70 Norway) with a 5 or 6 MHz matrix transducer probe. All assessments were performed by the same examiner, who was blinded to the clinical characteristics of the patients. Cardiac chamber quantification, Doppler echocardiography and M-mode echocardiographic measurements (left atrial diameter, aortic diameter, interventricular septal thickness, posterior wall thickness, left ventricular internal dimensions, tricuspid annular plane systolic excursion) were performed according to the established standards of the American Society of Echocardiography [22]. Left ventricular mass was calculated using the formula given by Devereux et al. according to the American Society of Echocardiography guidelines: left ventricular mass (g) = 0.81 [1.04 (interventricular septum thickness + posterior wall thickness + left ventricular internal dimension)3 − (left ventricular internal dimension)3] + 0.06. The left ventricular mass index was derived by dividing the left ventricular mass in grams by the patient’s body surface area. Relative wall thickness was defined as the ratio of the end-diastolic left ventricular posterior wall thickness to the left ventricular internal dimension [(2 × posterior wall thickness)/(left ventricular internal dimension)].

Statistical analysis

Statistical analyses were performed using the SPSS software v. 23 (IBM, Armonk NY). The variables were investigated using visual (histogram, probability plots) and analytic methods (Kolmogorov–Smirnov/Shapiro–Wilk’s test) to determine whether or not they were normally distributed. Descriptive analyses were presented using means and S.D.s for normally distributed variables and medians and interquartile range (IQR) for the non-normally distributed and ordinal variables. χ2 analysis and Student’s t test were used for the comparison of two parametric variables, while the Mann–Whitney U test was used in the presence of non-parametric data. Correlations between cIMT values and various continuous variables were investigated using Pearson and Spearman correlation analyses. P-values of <0.05 were accepted as significant.

Results

Demographics and clinical characteristics

Thirty-one patients [16 female (51.6%; female:male ratio 1.06)] diagnosed with childhood-onset BD were included in the study. All the patients (n = 31, 100%) were Turkish. The mean age at disease onset and at the time of diagnosis was 8.79 ± 4.31 years and 11.70 ± 3.25 years, respectively. Based on the cumulative disease characteristics, oral ulcer was the most common clinical finding (100%), followed by skin involvement (77.4%, n = 24), arthritis (54.8%, n = 17) and genital ulcers (48.4%, n = 14). Nine patients (29%) had a history of ocular involvement, and six patients (19.4%) had vascular involvement. The most common form of vascular involvement was sinus vein thrombosis (n = 3, 50%), followed by femoral vein involvement (2/6, 33.3%), descending abdominal aorta involvement (n = 1, 16.6%), iliac artery involvement (n = 1, 16.6%), popliteal artery involvement (n = 1, 16.6%) and brachial vein involvement (n = 1, 16.6%). The HLA-B51 allele was carried by 19 patients (61.3%), and 8 patients (25.8%) had a positive pathergy test.

We compared the patient demographics and clinical characteristics of BD patients based on the presence of vascular involvement. There was no statistical difference based on gender or age between the two groups. Patients with vascular involvement were more likely to have CNS involvement (16.6% parenchymal) (50%, n = 3 vs 8%, n = 2, P = 0.038) and had received more immunosuppressant therapy than those without (100%, n = 6 vs 36%, n = 9, P = 0.005). When we compared the laboratory levels at the time of study recruiting, the levels of very-low-density lipoprotein (VLDL) [21.50 mg/dl (17–27) vs 13 mg/dl (10–20), P = 0.026], triglycerides [105.5 mg/dl (87–135) vs 66 mg/dl (54–94), P = 0.021] and CRP [1.1 mg/dl (0.5–1.7) vs 0.4 mg/dl (0.2–0.7), P = 0.047] were higher and the level of high-density lipoprotein (HDL) [40.50 mg/dl (31–45) vs 46 (44–57), P = 0.035] was lower in patients with vascular involvement compared with the patients without vascular involvement. With respect to the other parameters [including leucocytes, haemoglobin, platelet count, serum homocysteine, total cholesterol, low-density lipoprotein (LDL) levels, and ESR] there were no statistically significant differences between the groups. The demographic and clinical characteristics are summarized in Table 1.

Table 1. Patients’ demographics, and clinical and laboratory characteristics according to vascular involvement

Characteristics	Vascular involvement	P-value	
Yes (n = 6)	No (n = 25)	
Gender, F/M	4/2	12/13	0.654	
Age at disease onset, years	12.23 (7.84–13.72)	9.18 (5.88–11.62)	0.516	
Age at diagnosis, years	12.45 (7.84–13.72)	12.21(9.88–13.88)	0.920	
Disease duration, months	70.98 (63.57–148.80)	75.47 (46.62–112.10)	0.484	
Delay in the diagnosis, months	11.98 (00–28.98)	17.97 (5.03–88.97)	0.342	
Age at the time of study, years	18.06 (17.18–20.06)	16.84 (11.50–18.35)	0.147	
Oral ulcer, n (%)	6 (100.0%)	25 (100.0%)	–	
Genital ulcer, n (%)	3 (50.0%)	12 (48.0%)	1.0	
Skin involvement, n (%)	4 (66.7%)	20 (80.0%)	0.596	
Erythema nodosum, n (%)	2 (33.3%)	12 (48.0%)	0.664	
Pathergy positivity, n (%)	2 (33.3%)	6 (24.0%)	0.634	
Ocular involvement, n (%)	2 (33.3%)	7 (28.0%)	1.0	
Arthritis, n (%)	2 (33.3%)	15 (60.0%)	0.370	
CNS involvement, n (%)	3 (50.0%)	2 (8.0%)	0.038	
HLA-B51 positivity, n (%)	4 (66.7%)	15 (60.0%)	1.0	
Leucocytes/mm3	5650 (4700–6200)	6400 (5500–7700)	0.176	
Haemoglobin, g/dl	13.25 (12.60–14.80)	13.50 (12.80–14.90)	0.822	
Platelets/mm3	213 000 (186 000–270 000)	252 000 (232 000–281 000)	0.089	
Total cholesterol, mg/dl	123 (118–148)	147 (133–168)	0.162	
HDL, mg/dl	40.50 (31–45)	46 (44–57)	0.035	
LDL, mg/dl	83 (79–101)	89 (82–104)	0.466	
VLDL, mg/dl	21.50 (17–27)	13 (10–20)	0.026	
Triglycerides, mg/dl	105.5 (87–135)	66 (54–94)	0.021	
Homocysteine, mmol/l	13.25 (9–21)	15 (9.7–16.5)	0.953	
ESR, mm/h	17.5 (2–24)	8 (4.12)	0.340	
CRP, mg/dl	1.1 (0.5–1.7)	0.4 (0.2–0.7)	0.047	
CS, n (%)	6 (100%)	19 (76%)	0.181	
Immunosuppressive, n (%)	6 (100%)	9 (36%)	0.005	
Colchicine, n (%)	4 (66.7%)	22 (88%)	0.202	
Continuous parameters are presented as median (interquartile range, IQR). Bold text highlights statistically significant values. aAll the laboratory tests were on the same day with cIMT. HDL: high-density lipoprotein, LDL: low-density lipoprotein, VLDL: very low-density lipoprotein.

Ambulatory blood pressure monitoring

Twenty-four-hour ABPM was performed in 29 BD patients. Among them, 10 patients (34.4%) had abnormal ABPM. Twenty-four-hour, daytime and nighttime MAP S.D. scores, SBP S.D. scores and DBP S.D. scores were statistically similar between the two groups. (Table 2). Seven patients were non-dippers (24.1%), and hypertension was detected in 5 BD (17.2%, 5/29) patients. Abnormal ABPM frequency (50%, n = 3 vs 30.4%, n = 7, P = 0.633), the frequency of non-dippers (33.3%, n = 2 vs 21.7%, n = 5, P = 0.612) and the frequency of hypertension (33.3%, n = 2 vs 13%, n = 3, P = 0.269) also did not differ significantly between patients with and without vascular involvement, respectively.

Table 2. Twenty-four-hour ambulatory blood pressure monitoring findings of patients with Behçet’s disease according to vascular involvement

Parameters	Vascular involvement	P-value	
Yes (n = 6)	No (n = 23)	
24-h				
  MAP, mm	87.0 ± 6.5	84.2 ± 4.9	0.130	
  SBP, mm	120.2 ± 13.0	120.2 ± 13.0	0.089	
  DBP, mm	69.5 ± 3.0	68.7 ± 4.3	0.607	
  HR, bpm	78.2 ± 6.8	83.3 ± 8.6	0.138	
  MAP S.D. score	0.55 ± 0.99	0.21 ± 0.73	0.196	
  SBP S.D. score	0.34 ± 1.68	–0.42 ± 0.80	0.196	
  DBP S.D. score	0.27 ± 0.54	0.19 ± 0.75	0.746	
  HR S.D. score	0.14 ± 0.78	0.48 ± 0.82	0.294	
Day-time				
  MAP, mm	91.2 ± 6.8	88.7 ± 5.7	0.144	
  SBP, mm	123.8 ± 13.1	117.04 ± 8.1	0.095	
  DBP, mm	74.0 ± 4.6	73.43 ± 5.0	0.705	
  HR, bpm	84.2 ± 7.7	88.4 ± 9.6	0.281	
  MAP S.D. score	0.42 ± 0.94	0.17 ± 0.78	0.225	
  SBP S.D. score	0.19 ± 1.57	–0.41 ± 0.85	0.187	
  DBP S.D. score	0.10 ± 0.80	0.09 ± 0.81	0.829	
  HR S.D. score	0.27 ± 0.78	0.42 ± 0.84	0.467	
Night-time				
  MAP, mm	76.8 ± 7.6	73.5 ± 4.3	0.291	
  SBP, mm	109.5 ± 13.2	100.7 ± 6.6	0.118	
  DBP, mm	58.7 ± 3.3	57.0 ± 3.8	0.317	
  HR, bpm	65.3 ± 5.1	71.6 ± 9.1	0.105	
  MAP S.D. score	0.78 ± 1.33	0.24 ± 0.64	0.419	
  SBP S.D. score	0.57 ± 1.81	−0.43 ± 0.62	0.282	
  DBP S.D. score	0.49 ± 0.59	0.19 ± 0.66	0.319	
  HR S.D. score	0.03 ± 0.49	0.51 ± 0.86	0.146	
Abnormal ABPM, n (%)	3 (50.0)	7 (30.4%)	0.633	
  Non-dipper, n (%)	2 (33.3)	5 (21.7%)	0.612	
  Hypertension, n (%)	2 (33.3)	3 (13.0%)	0.269	
ABPM: ambulatory blood pressure monitoring, DBP: diastolic blood pressure, HR: heart rate. MAP: mean arterial blood pressure, SBP: systolic blood pressure.

Echocardiography

Table 3 summarizes the standard M-mode, 2-dimensional and Doppler echocardiographic findings for BD patients with and without vascular involvement. Patients with vascular involvement had a significantly higher left ventricle outflow Doppler velocity [1.25 ± 0.05 vs 1.10 ± 0.31 (P = 0.002)] and velocity time integral for the aorta [24.45 ± 1.50 vs 20.43 ± 3.53 (P = 0.006)].

Table 3. Echocardiography findings of patients with Behçet’s disease according to vascular involvement

Parameters	Vascular involvement	P-value	
Yes (n = 6)	No (n = 25)	
TAPSE, mm	19.60 ± 3.51	21.65 ± 3.31	0.216	
TAPSE S.D. score	–2.25 ± 1.62	–0.80 ± 1.69	0.099	
LVM, g	121 ± 30.01	114.12 ± 53.18	0.368	
LVM S.D. score	–0.58 ± 0.93	–0.96 ± 2.12	0.653	
LVMI, g/m2	70.33 ± 8.82	74.56 ± 21.53	0.438	
LAtr diameter, cm	2.75 ± 0.30	2.94 ± 0.68	0.636	
LAtr diameter S.D. score	0.40 ± 0.69	0.88 ± 0.94	0.169	
Ao diameter, mm	2.86 ± 0.15	2.73 ± 0.32	0.211	
Ratio of LAtr to Ao diameter	0.96 ± 0.1	1.06 ± 0.1	0.052	
Relative wall thickness	0.39 ± 0.07	0.40 ± 0.11	0.960	
IVST-D, cm	0.88 ± 0.13	0.88 ± 0.16	0.878	
IVST-D S.D. score	0.53 ± 0.20	0.85 ± 0.51	0.121	
  IVST-S, cm	1.35 ± 0.15	1.28 ± 0.26	0.348	
IVST-S S.D. score	1.00 ± 0.40	1.05 ± 0.74	0.940	
LVID-D, cm	4.37 ± 0.41	4.16 ± 0.72	0.366	
LVID-D S.D. score	–1.16 ± 1.35	–1.18 ± 1.63	0.337	
  LVID-S, cm	2.73 0.36	2.56 0.46	0.391	
LVID-S S.D. score	–0.85 ± 1.61	–1.04 ± 1.85	0.617	
  LVPWT-D, cm	0.84 ± 0.13	0.82 ± 0.16	0.745	
LVPWT-D S.D. score	0.74 ± 0.68	0.95 ± 0.69	0.51	
LVPWT-S, cm	1.35 ± 0.19	1.22 ± 0.28	0.244	
LVPWT-S S.D. score	–0.03 ± 0.49	–0.33 ± 1.20	0.764	
Diastolic arterial pressure, mm	73.33 ± 7.53	71.40 ± 9.19	0.721	
Systolic arterial pressure, mm	110.83 ± 11.14	105.00 ± 9.46	0.241	
Mitral inflow E wave, m/s	0.88 ± 0.09	0.83 ± 0.12	0.299	
Mitral inflow A wave, m/s	0.60 ± 0.06	0.55 ± 0.08	0.212	
Ratio of E to A	1.48 ± 0.24	1.51 ± 0.26	0.775	
LVOT velocity, m/s	1.25 ± 0.05	1.10 ± 0.31	0.020	
LVOT VTI, cm	24.45 ± 1.50	20.43 ± 3.53	0.006	
IVCT, ms	65.33 ± 9.44	65.84 ± 13.24	0.841	
IVRT, ms	71.17 ± 4.26	62.88 ± 11.14	0.068	
Bold text highlights statistically significant values. BD: Behçet’s disease; Ao: aorta, TAPSE: tricuspid annular plane systolic excursion; LVM: left ventricular mass; LVMI: left ventricular mass index; LAtr: left atrium; IVST-D: interventricular septum thickness at end-diastole; IVST-S: interventricular septum thickness at end-systole; LVID-D: left ventricular internal dimension at end-diastole; LVID-S: left ventricular internal dimension at systole; LVPWT-D: left ventricular posterior wall thickness in diastole; LVPWT-S: left ventricular posterior wall thickness in systole; LVOT: left ventricle outflow tract; VTI: velocity time integral; IVCT: isovolumetric contraction time; IVRT: isovolumetric relaxation time.

Carotid intima-media thickness

The cIMT values of the right and left common carotid arteries in BD patients with vascular involvement (0.41 ± 0.5 mm and 0.44 ± 0.7 mm) respectively, and in BD patients without vascular involvement (0.42 ± 0.6 mm and 0.42 ± 0.7 mm) respectively, were not significantly different (Table 4). The prevalence of elevated cIMT (>90th percentile) in patients with and without vascular involvement was statistically similar (33.3% vs 28.0% P = 0.798) (Fig. 1). cIMT values in BD patients with hypertension (0.50 ± 0.7 mm) were significantly higher than in BD patients without hypertension (0.41 ± 0.5 mm) (P = 0.019). Spearman correlation analyses were performed to find the parameters associated with cIMT. cIMT values were positively correlated only with the body mass (r = 0.465, P = 0.008), height (r = 0.364, P = 0.044), and left ventricular mass S.D. score (r = 0.395; P = 0.028). However, they were not correlated with disease duration, age at onset, or age at diagnosis.

Figure 1. The prevalence of abnormal carotid IMT in patients with vascular involvement compared with patients without vascular involvement (33.3% vs 28.0% P = 0.798). carotid IMT: carotid intima-media thickness

Table 4. Carotid intima media thickness results of patients with Behçet’s disease according to vascular involvement

Parameters	Vascular involvement	P-value	
Yes (n = 6)	No (n = 25)	
cIMT, mm	0.43 ± 0.5	0.42 ± 0.7	0.841	
cIMT S.D. score for age	0.70 ± 1.08	0.68 ± 1.33	0.764	
cIMT S.D. score for height	0.78 ± 0.99	0.68 ± 1.28	0.756	
cIMT: carotid intima-media thickness.

Discussion

BD is a very heterogeneous disease in itself and may involve various systems and organs. Patients with BD experience long-term morbidity and even mortality caused by different forms of cardiovascular diseases [23]. Our aim was to find out whether paediatric BD patients with and without vascular involvement had the same risk for cardiovascular comorbidity independent of the contribution of traditional risk factors. In the present study, we showed that 10 patients (34.4%) had abnormal ABPM. However, the carotid IMT and 24-hour ABPM results were not significantly different in paediatric BD patients with and without vascular involvement. In the echocardiographic evaluation, the velocity and velocity time integral of the left ventricle outflow tract differed significantly between the two groups. These findings suggest that paediatric BD patients with vascular involvement may have more increased arterial stiffness compared with BD patients without vascular involvement.

In our study, BD patients with vascular involvement had higher levels of VLDL and triglyceride and lower levels of HDL. Furthermore, although, all patients had inactive disease at the time of study recruiting, patients with vascular involvement had significantly higher levels of CRP. One of the most common causes of mortality in BD is associated with vascular involvement, and it merits more intense CS and immunosuppressive therapy [24]. It is well known that CS therapy may increase total cholesterol and its modifications. Furthermore, previous studies have reported that patients with systemic vasculitis have decreased levels of HDL cholesterol [25]. Increased levels of lipids may have a proinflammatory effect on the vessel wall and contribute to the increased levels of CRP [26]. Therefore, the impaired lipid profile and higher levels of CRP in our patients with vascular involvement may be attributed both to the inflammatory background of BD and possibly to the CS and immunosuppressive therapy.

Atherosclerosis is a chronic inflammatory disease of the arterial intima. Even in children, fatty streaks (which are premature lesions of atherosclerosis) may be present. In the presence of triggering factors, the fatty streak may progress to a complicated atherosclerotic plaque later in life. Systemic inflammatory diseases and increased production of CRP may also accelerate premature atherosclerosis, as has been shown in SLE, RA, granulomatosis with polyangiitis, and Takayasu arteritis [26, 27]. However, there is conflicting evidence regarding the issue of early atherosclerosis in BD [28]. Frequency of coronary atherosclerosis was found to be relatively low even in young male BD patients with major vessel disease [29]. On the other hand, a recent meta-analysis revealed that BD patients had overall thicker carotid intima-media compared with control groups [28].

Considering the inflammatory damage to the vessel wall in patients with BD vasculitis, it is expected that these patients were more at risk of premature atherosclerosis compared with BD patients without vascular involvement. Venous wall thickness (VWT) in lower extremities was shown by Alibaz-Oner et al. to be increased in adult BD patients, and these authors suggested that VWT can be used as a diagnostic tool for BD [30]. Recently, Atalay et al. evaluated VWT in the lower extremities in paediatric BD and found that increased VWT was present not only in BD patients with vascular involvement but also in those without [31]. Similarly, Caliskan et al. showed that IMT results were similar in adult BD patients with and without vascular involvement [32]. In our study, the prevalence of abnormal cIMT in patients with and without vascular involvement was statistically similar, as well. These results may reflect the presence of ongoing subclinical vessel wall inflammation in all BD patients, regardless of vascular involvement.

We also screened all patients with routine echocardiography and aimed to determine whether there was a clinical difference in terms of early cardiac manifestations in BD patients with and without vascular involvement. The velocity and velocity time integral of the left ventricle outflow tract were significantly increased in the patients with vasculitis. Several authors have demonstrated that arterial stiffness is increased in BD. Yılmaz et al. reported that patients with active systemic BD involving two or more organs had advanced arterial stiffness [33]. Ikonomidis et al. showed that BD patients had decreased aortic elastic properties and left ventricular diastolic function compared with control groups. Furthermore, they showed that BD patients with vascular involvement had higher isovolumetric relaxation time [34]. It would be reasonable to associate vascular BD with the abnormalities in the echocardiography observed in our study. Vasculitis of the vasa vasorum may cause fibrosis, degradation of the elastin within the aortic wall, and lead to the increased arterial stiffness.

A recent meta-analysis demonstrated a significant association between BD and hypertension [35]. In the present study, we also found that 10 patients (34.4%) had abnormal ABPM. Seven patients were non-dippers (24.1%), and hypertension was detected in 5 BD (17.2%, 5/29) patients, despite having no known preexisting hypertension. Moreover, cIMT values in BD patients with hypertension were significantly higher than in BD patients without hypertension. When comparing BD patients with and without vascular involvement the frequencies of abnormal ABPM, non-dipping and hypertension were not significantly different. Our results showed that the use of ABPM in patients with BD allows us to diagnose hypertension earlier and protect them from the increased risk of atherosclerosis.

Our study has several limitations. First, we did not have a healthy control group for comparison. Second, due to the rarity of the disease in childhood, the number of patients with vascular involvement was relatively small. Third, the findings of our study might have been influenced by the different immunosuppressive treatment strategies these patients were receiving.

In conclusion, although paediatric BD patients with vascular involvement may tend to be more predisposed to cardiovascular comorbidity, our findings suggest that there is ongoing subclinical vessel wall inflammation even in patients without vascular involvement. BD has unique features, with significant inflammation in all organ systems, and these patients should be evaluated for cardiovascular risk factors regardless of the involved systems. We suggest that ABPM may accurately identify hypertension and increased cardiovascular risk in BD patients. We need long-term follow-up studies in larger groups to firmly assess the risk of future cardiovascular comorbidities in paediatric-onset BD.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.

Funding

No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.

Disclosure statement: The authors have declared no conflict of interest.
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