Edited by: Peter Korsten, Nephrology and Rheumatology University Medical Center Göttingen, Germany
Reviewed by: Silvia Piantoni, University of Brescia, Italy; Chris Wincup, University College London, United Kingdom
This article was submitted to Rheumatology, a section of the journal Frontiers in Medicine
†These authors have contributed equally to this work
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease affecting multiple organ systems which often affects young females (
Antiphospholipid syndrome antibodies (aPL) form a heterogeneous group of antibodies targeting phospholipid-binding proteins and phospholipids. The aPL included in the APS classification criteria are lupus anticoagulant, anticardiolipin [immunoglobulin G (IgG)/IgM], and anti–β2-glycoprotein I antibodies (IgG/IgM) (
High-frequency ultrasound (US) provides an opportunity to distinguish atherosclerosis from inflammation in the vessel walls. Measurement of intima-media thickness (IMT) with high-frequency US in the common carotid artery constitutes a validated method to assess early atherosclerosis (
A hypertensive hypertrophic response of medial cells can be seen in early atherosclerosis and can be quantified by IMT-measurement, while plaques are often observed in a later phase and may be related to inflammation, oxidation, endothelial dysfunction and/or smooth muscle cell proliferation (
Herein, we aimed to evaluate whether an extended US protocol (including examination of carotid arteries, central neck arteries as well as femoral arteries) may add valuable information regarding the type of vessel affection among patients with SLE in a quiescent phase of their disease.
In this cross-sectional study, we included 60 patients (52 women, 8 men; mean age 43.2 ± 11.3 years), diagnosed with SLE based on fulfillment of the 1982 American College of Rheumatology (ACR) and/or the 2012 Systemic Lupus Collaborating Clinics (SLICC) classification criteria as detailed in
Sixty patients included in KLURING were selected and divided into 3 phenotypic subgroups with different SLE manifestations. The subgroups were matched between each other 1:1:1 according to sex and age; 20 cases meeting the renal disorder ACR criterion for LN (
Sixty healthy age- and sex-matched (1:1 to the 60 SLE cases), non-medicated controls without clinical signs of inflammatory or atherosclerotic disease (52 women and 8 men; mean age 42.9 ± 11.5 years), were examined using the same protocol as for the patients. The healthy controls were all of Caucasian ethnicity and had all been recruited from the hospital staff.
We obtained demographic data from all subjects regarding height, weight, waist circumference and sagittal abdominal diameter. Variables concerning age, sex, smoking habits and ongoing pharmacotherapy were collected. Blood pressure was determined with oscillometric technique (Dinamap PRO 200 Monitor, Critikon, Tampa, FL, USA).
Standard cardiovascular and inflammatory laboratory test with measurements of total cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), plasma creatinine and C-reactive protein with high sensitive technique (hsCRP) were collected after 12-h overnight fasting. Presence of serological disease activity, with anti–double-stranded DNA antibodies using addressable laser bead immunoassay (FIDIS™ Connective profile, Solonium software version 1.7.1.0, Theradiag, Croissy-Beaubourg, France) and plasma analyses complement protein 3 (C3) and 4 (C4), was controlled for at the closest regular visit to rheumatologist (
For the US measurements, a GE Logic E9 US system (LOGIQ E9 XDclear 2.0 General Electric Medical Systems US, Wauwatosa, WI, USA) with linear transducer L2-9 MHz was used. For the aortic arch, a C1-6 MHz transducer was used. IMT was measured in common carotid artery (CCA), internal carotid artery (ICA), subclavian artery (SCA), axillar artery (AxA), common femoral artery (CFA), superficial femoral artery (SFA) and the aortic arch. Measuring principles are shown in
In areas free of plaques with IMT ≥0.9 mm for carotid and central arteries, and ≥1.2 mm for the aortic arch, the vessel wall was assessed regarding echogenicity (low–medium–high). Furthermore, distribution and presence of fibrotic stripes were noted. The cutoff value of ≥0.9 mm was chosen due to the latest European Society of Hypertension/European Society of Cardiology (ESH/ESC) hypertension guidelines (
A standardized examination procedure was used in all individuals. The participant had to rest 15 min before the test which was performed in a room with a temperature of 25°C, dim lighting and no outer disturbances. All participants were asked to refrain from coffee 4 h prior to the measurements.
The same vascular sonographer performed all US examinations and offline measurements performed after the exam. The sonographer was blinded to which classification criteria the patients with SLE fulfilled, but not blinded to whether the participants were patients or controls.
Oral and written informed consent was obtained from all patients and healthy controls. The study protocol was performed according to the Declaration of Helsinki and approved by the Regional Ethics Board in Linköping (ref. M75-08, 2013/33-31 and ref. 2017/572-32).
According to the central limit theorem, sufficiently many subjects were included to allow use of methods that relay on the normal distribution. Demographic values and IMT are presented as mean ± SD. Differences between the whole SLE group and controls were calculated using Student's
Detailed characteristics of included patients and controls presented as mean±SD or
Age at examination (years) | 43.2 ± 11.3 | 43.0 ± 11.4 | 41.6 ± 10.4 | 45.2 ± 12.2 | 42.9 ± 11.7 |
Female gender, |
52 (87) | 52 (87) | 18 (90) | 15 (75) | 19 (95) |
Duration of SLE (years) | 12.0 ± 9.4 | N/A | 10.7 ± 8.1 | 15.6 ± 12.2 | 9.6 ± 6.3 |
SDI | 0.8 ± 1.1 | N/A | 0.6 ± 0.9 | 1.5 ± 1.4 | 0.4 ± 0.5 |
SLEDAI-2K | 2.0 ± 2.1 | N/A | 1.6 ± 2.1 | 2.1 ± 2.4 | 2.2 ± 1.7 |
Serologically active clinically quiescent SLE, |
29 (48) | N/A | 13 (65) | 10 (50) | 6 (30) |
Body mass index (BMI) (kg/m2) | 26.0 ± 4.2** | 24.0 ± 3.3 | 26.5 ± 3.4* | 25.6 ± 4.0 | 25.8 ± 5.1 |
Waist circumference (cm) | 92.4 ± 12.1*** | 83.0 ± 10.0 | 93.2 ± 11.2** | 92.2 ± 12.8* | 91.8 ± 12.7 |
Sagittal abdominal diameter (cm) | 20.6 ± 3.9** | 18.8 ± 2.7 | 20.7 ± 3.7 | 20.6 ± 3.9 | 20.6 ± 4.3 |
Ever smoker (former or current), n (%) | 14 (23) | 0 | 4 (20) | 3 (15) | 7 (35) |
Systolic blood pressure (mm Hg) | 115 ± 26 | 112 ± 18 | 117 ± 17 | 113 ± 32 | 116 ± 29 |
Diastolic blood pressure (mm Hg) | 73 ± 11* | 68 ± 8 | 74 ± 12 | 73 ± 10 | 72 ± 9 |
Diabetes mellitus, |
1 (2) | 0 | 0 | 1 (5) | 0 |
Raynaud's phenomenon, |
16 (27) | 9 (15) | 4 (20) | 5 (25) | 7 (35) |
Estimated glomerular filtration rate (mL/min/1,73 m2) | 84 ± 16 | Not available | 85 ± 14 | 79 ± 18 | 87 ± 13 |
Total cholesterol (mmol/L) | 4.7 ± 1.0 | 4.9 ± 1.1 | 4.5 ± 1.0 | 4.7 ± 0.8 | 4.9 ± 1.1 |
High-density lipoprotein (HDL) (mmol/L) | 1.6 ± 0.5 | 1.7 ± 0.4 | 1.5 ± 0.4 | 1.6 ± 0.5 | 1.6 ± 0.4 |
Low-density lipoprotein (LDL) (mmol/L) | 2.6 ± 0.8 | 2.6 ± 0.9 | 2.5 ± 0.9 | 2.5 ± 0.7 | 2.9 ± 0.9 |
Triglycerides (TG) (mmol/L) | 1.1 ± 0.7 | 1.2 ± 0.6 | 1.2 ± 0.6 | 1.3 ± 1.0 | 0.9 ± 0.4 |
High-sensitivity CRP (mg/L) | 2.2 ± 2.8 | 2.0 ± 3.7 | 1.4 ± 1.3 | 2.7 ± 3.4 | 2.5 ± 3.2 |
Anti-dsDNA (IU/mL) | 86 ± 200 | N/A | 71 ± 115 | 89 ± 200 | 86 ± 202 |
Complement protein 3 (g/L) | 1.0 ± 0.2 | N/A | 1.0 ± 0.2 | 0.9 ± 0.2 | 1.0 ± 0.2 |
Complement protein 4 (g/L) | 0.2 ± 0.1 | N/A | 0.1 ± 0.1 | 0.2 ± 0.1 | 0.2 ± 0.1 |
Antimalarial agents, |
54 (90) | 0 | 20 (100) | 16 (80) | 18 (90) |
Antihypertensives, n (%) | 20 (33) | 0 | 11 (55) | 6 (30) | 3 (15) |
Beta-blockers, |
5 (8) | 0 | 1 (5) | 1 (5) | 3 (15) |
ARB/ACE inhibitors, |
15 (25) | 0 | 9 (45) | 4 (20) | 2 (10) |
Other antihypertensives, |
4 (7) | 0 | 2 (10) | 1 (5) | 1 (5) |
Glucocorticoid therapy |
31 (52) | 0 | 12 (20) | 9 (45) | 10 (50) |
4.5 | 0 | 5.4 | 3.8 | 4.2 | |
Warfarin therapy, |
11 (18) | 0 | 1 (5) | 10 (50) | 0 |
Antiplatelet therapy, |
11 (18) | 0 | 5 (25) | 6 (30) | 0 |
Statin therapy |
5 (8) | 0 | 2 (10) | 3 (15) | 0 |
DMARD therapy, |
27 (45) | 0 | 11 (55) | 9 (45) | 7 (35) |
Mycophenolate mofetil, |
16 (27) | 0 | 11 (55) | 4 (20) | 1 (5) |
Methotrexate, |
5 (8) | 0 | 0 | 1 (5) | 4 (20) |
Azathioprine, |
3 (5) | 0 | 0 | 2 (10) | 1 (5) |
Sirolimus, |
2 (3) | 0 | 0 | 1 (5) | 1 (5) |
Dehydroepiandrosterone, |
1 (2) | 0 | 1 (2) | 0 | 0 |
Biologics, |
4 (7) | 0 | 3 (15) | 1 (5) | 0 |
Bortezomib, |
1 (2) | 0 | 1 (5) | 0 | 0 |
Rituximab, |
1 (2) | 0 | 1 (5) | 0 | 0 |
Belimumab, |
2 (3) | 0 | 1 (5) | 1 (5) | 0 |
Basic demographics, laboratory data and ongoing medical therapies are shown in
As shown in
IMT in measured vessels.
CCA | 0.56 ± 0.10 | 0.54 ± 0.13 | 0.54 ± 0.07 | 0.58 ± 0.11 | 0.55 ± 0.10 |
ICA | 0.52 ± 0.17 |
0.45 ± 0.09 | 0.56 ± 0.20 |
0.53 ± 0.13 |
0.47 ± 0.12 |
SCA | 0.58 ± 0.19 |
0.53 ± 0.13 | 0.56 ± 0.08 | 0.61 ± 0.16 | 0.57 ± 0.13 |
AxA | 0.49 ± 0.10 | 0.48 ± 0.10 | 0.50 ± 0.15 | 0.52 ± 0.15 | 0.54 ± 0.21 |
Aortic arch | 1.21 ± 0.63 |
0.98 ± 0.25 | 1.27 ± 1.05 | 1.26 ± 0.29 |
1.11 ± 0.24 |
CFA | 0.57 ± 0.23 |
0.49 ± 0.11 | 0.56 ± 0.22 | 0.62 ± 0.21 |
0.57 ± 0.22 |
SFA | 0.44 ± 0.11 | 0.42 ± 0.10 | 0.44 ± 0.12 | 0.45 ± 0.10 | 0.44 ± 0.12 |
In relation to SLE phenotypes, IMT was still increased in the APS group compared to controls in CFA (
The reproducibility between two repeated measurements of IMT in the whole group of patients showed a difference of mean 0.06 ± 0.19 mm in right and left CCA (not significant). In the healthy controls this value was 0.08 ± 0.06 (not significant).
Increased IMT ≥0.9 mm observed in SLE patients showed a medium echogenic, homogenous wall thickening that can be seen in inflammatory vascular disease (
Number of SLE patients with each phenotypic subgroup and controls with areas showing increased IMT (≥0.9 mm for CCA, ICA, SCA, CFA; ≥1.2 mm for the aortic arch). Plaques (gray areas) were distributed as follows: right/left carotid bifurcation: SLE,
Fibrotic stripes combined with medium echogenic homogenous wall thickening (of inflammatory appearance) (
Fifty percentage of the subjects with echogenic homogenous wall thickening and fibrotic stripes had no atherosclerotic plaques. Atherosclerotic plaques (
The occurrence of plaques among patients and controls shown in relation to age groups.
The occurrence of plaques shown in relation to duration of SLE (χ2,
Relation between traditional and disease dependent risk factors and IMT are shown in
IMT related to background variables, traditional risk factors, laboratory tests A and medical treatment in an univariate regression model for internal carotid artery (ICA), common carotid artery (CCA) and common femoral artery (CFA) among all 60 patients with SLE.
Age at examination (years) | 0.005 | 0.003 | 0.006 | <0.001 | 0.012 | <0.001 |
Female gender | −0.045 | 0.058 | −0.085 | 0.058 | 0.074 | NS |
Duration of SLE (years) | 0.005 | 0.016 | 0.003 | 0.053 | 0.007 | 0.051 |
SDI | 0.029 | NS | 0.020 | NS | 0.065 | 0.019 |
Body mass index (BMI) (kg/m2) | 0.001 | NS | 0.002 | NS | 0.022 | 0.002 |
Waist circumference (cm) | 0.002 | NS | 0.002 | NS | 0.010 | <0.001 |
Sagittal abdominal diameter (cm) | 0.007 | NS | 0.003 | NS | 0.032 | <0.001 |
Ever smoker (former or current) | 0.087 | 0.066 | 0.012 | NS | 0.035 | NS |
Systolic blood pressure (mm Hg) | 0.519 | NS | 0.001 | NS | 0.002 | 0.035 |
Diastolic blood pressure (mm Hg) | 0.002 | NS | 0.002 | NS | 0.012 | <0.001 |
Raynaud's phenomenon | 0.104 | 0.020 | 0.095 | 0.006 | 0.063 | NS |
Estimated glomerular filtration rate (mL/min/1,73 m2) | −0.03 | 0.026 | 0.002 | 0.082 | 0.012 | <0.001 |
Total cholesterol (mmol/L) | 0.036 | 0.084 | 0.043 | 0.005 | 0.116 | <0.001 |
High-density lipoprotein (HDL) (mmol/L) | 0.019 | NS | 0.541 | NS | 0.113 | 0.078 |
Low-density lipoprotein (LDL) (mmol/L) | 0.028 | NS | 0.038 | 0.039 | 0.087 | 0.016 |
Triglycerides (TG) (mmol/L) | 0.045 | NS | 0.057 | 0.006 | 0.106 | 0.008 |
High-sensitivity CRP (mg/L) | −0.003 | 0.026 | −0.004 | 0.476 | 0.022 | 0.031 |
Antimalarial agents | −0.105 | NS | −0.043 | NS | −0.126 | NS |
Antihypertensives | −0.026 | NS | 0.003 | NS | 0.155 | 0.018 |
Beta-blockers | 0.106 | NS | 0.079 | NS | 0.321 | 0.005 |
ARB/ACE inhibitors | 0.016 | NS | 0.007 | NS | 0.170 | 0.012 |
Other antihypertensives | −0.083 | NS | −0.049 | NS | −0.076 | NS |
Glucocorticoid therapy | −0.018 | NS | −0.012 | NS | 0.092 | NS |
Mean daily Prednisolone dose (mg) | −0.007 | NS | −0.004 | NS | 0.014 | NS |
Warfarin therapy | 0.003 | NS | 0.018 | NS | 0.042 | NS |
Antiplatelet therapy | −0.010 | NS | 0.027 | NS | 0.047 | NS |
Statin therapy | 0.093 | NS | 0.063 | NS | 0.213 | 0.065 |
DMARD therapy | 0.023 | NS | 0.001 | NS | −0.019 | NS |
In the univariate analysis of CFA, SDI, antihypertensive treatment, β-blocking therapy, Angiotensin II receptor blocker (ARB)/Angiotensin-converting enzyme (ACE) inhibitor treatment, BMI, waist circumference, sagittal abdominal diameter, systolic and diastolic blood pressure, cholesterol, LDL, triglycerides, estimated glomerular filtration rate (GFR) and hsCRP were all related to IMT. However, when all significant variables were included in a multiple linear regression model, age (B = 0.006,
In multiple analysis of CCA, age (B = 0.005,
In the univariate analysis, duration of SLE significantly influenced IMT in ICA but not in CCA or CFA, where the
As demonstrated in
Plaque occurrence related to background variables, tradtional risk factors, laboratory variables and ongoing medical treatment analyzed with univariate logistic regression.
Age at examination (years) | 0.106 | 0.003 |
Female gender | 0.693 | NS |
Duration of SLE (years) | 0.087 | 0.009 |
SDI | 0.370 | NS |
Body mass index (BMI) (kg/m2) | 0.121 | NS |
Waist circumference (cm) | 0.102 | 0.001 |
Sagittal abdominal diameter (cm) | 0.227 | 0.006 |
Ever smoker (former or current) | 2.005 | 0.003 |
Systolic blood pressure (mm Hg) | 0.011 | NS |
Diastolic blood pressure (mm Hg) | 0.012 | <0.001 |
Raynaud's phenomenon | 1.253 | 0.049 |
Estimated glomerular filtration rate (mL/min/1,73m2) | −0.017 | NS |
Total cholesterol (mmol/L) | 0.721 | 0.026 |
High-density lipoprotein (HDL) (mmol/L) | −0.446 | NS |
Low-density lipoprotein (LDL) (mmol/L) | 0.689 | 0.061 |
Triglycerides (TG) (mmol/L) | 1.115 | 0.026 |
High-sensitivity CRP (mg/L) | −0.009 | NS |
Antimalarial agents | 0.560 | NS |
Antihypertensives | 0.847 | NS |
Beta-blockers | 1.682 | NS |
ARB/ACE inhibitors | 0.981 | NS |
Other antihypertensives | 1.196 | NS |
Glucocorticoid therapy | 0.827 | NS |
Mean daily Prednisolone dose (mg) | 0.131 | NS |
Warfarin therapy | 0.145 | NS |
Antiplatelet therapy | 0.189 | NS |
Statin therapy | 0.767 | NS |
DMARD therapy | 0.629 | NS |
When all significant variables were included in a multivariate logistic regression model, age (B = 0.109,
In this study of well-characterized SLE patients, the great majority with clinically inactive disease, thicker IMT detected with US was observed in ICA, CFA, SCA, and the aortic arch compared to healthy controls, whereas IMT in CCA did not differ. By using this protocol, we were able to detect widespread vascular affection as measured with increased IMT, affected vessel wall appearance, and atherosclerotic plaques. The appearance of the vessel walls in patients with SLE has previously not been studied in detail.
A pathologic cutoff value of IMT ≥0.9 mm was chosen for CCA, ICA, SCA, and CFA according to the latest ESH/ESC hypertension guidelines (
Previous studies used US in SLE for both risk assessment and follow-up (
Areas of increased IMT (≥0.9 mm in CCA, ICA, SCA, and CFA; ≥1.2 mm in the aortic arc) without atherosclerotic plaques showed regular wall thickening of medium echogenicity. We have recently shown that an extended US protocol is of value for the assessment of giant cell arteritis (
We did not find any differences with regard to vessel wall appearance between SLE patients and matched controls. The intima media among SLE cases was smooth and homogeneous with discrete increased thickness, and fibrotic stripes were usually not observed. This appearance can be seen in inflammatory diseases, with increasing age, as an early sign of atherosclerosis, or due to hypertrophy of the arterial wall (
The hyperechogenic fibrotic stripes seen in CFA of some patients were similar to those seen in arteritis (
The pathogenetic mechanisms of increased IMT in SLE are not clear. Age influenced IMT of all vessel areas. When adjusting for age, only a few traditional and SLE-related risk factors influenced IMT of SCA, AxA, the aortic arch, and SFA. However, in univariate analysis of CFA, IMT was influenced by age, SDI, antihypertensive therapy, β-blocking therapy, ARB/ACE inhibitor treatment, BMI, waist circumference, sagittal abdominal diameter, systolic and diastolic blood pressure, cholesterol, LDL, triglycerides, estimated GFR, and hsCRP. In the multivariate analysis, four factors remained significant as explaining factors for IMT in CFA: age, sagittal abdominal diameter, diastolic blood pressure, and cholesterol. In CCA, age, male sex, and presence of Raynaud remained as significant explaining factors, whereas smoking habits did not. None of the controls and 14/60 SLE cases (23%) had been tobacco smokers, and most of them had finished smoking.
In the univariate analysis only, duration of SLE influenced IMT of ICA but did not reach significance in CCA or CFA (
Concerning occurrence of plaques, similar risk factors were observed as for increased IMT in CFA. Thus, pathogenic mechanisms promoting atherosclerosis seems more likely to contribute to increased IMT than inflammation
Measuring IMT with US has low interobserver and intraobserver variability (
The cross-sectional design and the rather low number of examined individuals constitute limitations of the present study. Although the SLE patients were well-matched to the healthy control group, slightly higher measurements regarding waist circumference, sagittal abdominal diameter, and BMI were recorded among the SLE cases. The assessment of the vessel walls and the grading of echogenicity are per definition subjective. Interobserver variability was not possible to study in this investigation as the same sonographer did all online and offline measurements. In contrast, the well-characterized population and the patients' universal access to health care constitute strengths of the present study.
Among SLE patients without presence of plaques, high-frequency US of multiple arterial areas revealed increased wall thickness with predominantly medium echogenic appearance highlighting possible inflammation or early atherosclerosis. Our findings in CFA emphasize the importance of examining several areas of the arterial tree, which could have implications for clinical practice. Increased number of plaques was observed in SLE compared to age- and sex-matched healthy controls. We found similar risk factors for increased IMT and occurrence of plaques, possibly indicating atherosclerotic mechanisms rather than inflammation, but atherosclerosis and inflammation appear to be closely interrelated. These data call for confirmation, and careful follow-up is needed before firm conclusions regarding cardiovascular management can be drawn.
All datasets generated for this study are included in the article/
The studies involving human participants were reviewed and approved by The Regional Ethics board in Linköping. The patients/participants provided their written informed consent to participate in this study.
CSv: study design, methodology, investigation, formal analysis, and manuscript writing. PE and CSj: study design, investigation, formal analysis, manuscript writing, and supervision. HZ: study design, methodology, investigation, formal analysis, manuscript writing, and supervision. All authors contributed to the article and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We acknowledge Marianne Petersson for logistic help when planning and performing the study, for blood sampling and for taking care of the patients and controls at their visits to the Rheumatology unit. Senior Professor of Rheumatology Thomas Skogh and Nora Östrup are both acknowledged for kindly reviewing the manuscript.
The Supplementary Material for this article can be found online at:
Angiotensin-converting enzyme
Antiphospholipid syndrome
Angiotensin II receptor blocker
Antiphospholipid antibodies
Axillar artery
Common carotid artery
Common femoral artery
High sensitive C-reactive protein
Cardiovascular disease
High-density lipoprotein
Internal carotid artery
Intima-media thickness
Clinical Lupus Register In North-eastern Gothia
Low-density lipoprotein
Lupus Nephritis
Magnetic resonance imaging
Positron emission tomography
Subclavian artery
Superficial femoral artery
Systemic Lupus International Collaborating Clinics
Systemic lupus erythemathosus
Ultrasound.