Ischemic Arterial Events and Atherosclerosis in Patients With Systemic Sclerosis

A Population-Based Case-Control Study

Annica Nordin; Kerstin Jensen-Urstad; Lena Björnådal; Susanne Pettersson; Anders Larsson; Elisabet Svenungsson

Arthritis Res Ther. 2013;15(4)

Abstract and Introduction

Abstract

Introduction: While microvascular disease is well described in systemic sclerosis (SSc), it is still unclear whether the occurrence of ischemic macrovascular events and atherosclerosis is enhanced among patients with SSc.

Methods: In this study, 111 SSc patients (74% of prevalent cases in Stockholm County) and 105 age- and sex-comparable population controls were investigated. Previous ischemic arterial events were tabulated. As surrogate measures of atherosclerosis, plaque occurrence and intima-media thickness (IMT) were determined with carotid ultrasound and the ankle-brachial index (ABI) was calculated. Traditional cardiovascular risk factors were recorded and we also measured biomarkers indicating systemic inflammation and endothelial activation/dysfunction.

Results Mean age was 62 ± 12 years for patients and controls. Ischemic arterial events were more common, due to increased occurrence of ischemic heart disease (IHD) and ischemic peripheral vascular disease (IPVD), in the patient group (12% vs. 4%, P = 0.03 and 9% vs. 0%, P = 0.003 respectively). On a group level, there was no difference regarding the occurrence of ischemic cerebrovascular disease, the frequency of plaques, IMT or ABI between SSc patients and controls. Subgroup analyses revealed that patients with anticentromere antibodies (ACA+) had more plaques and more ischemic arterial events compared to other SSc patients (67% vs. 39% and 32% vs. 11%; P = 0.006 and P = 0.01, respectively) and compared to controls (67% vs. 41% and 32% vs. 7%, P = 0.02 and P = 0.0003, respectively). Biomarkers of inflammation/endothelial activation were generally increased among SSc patients.

Conclusions: Patients with SSc are at enhanced risk for IHD and IPVD. The ACA+ SSc subgroup was particularly affected with both ischemic arterial events and premature atherosclerosis. The microvascular vulnerability of ACA+ patients is previously well documented. We demonstrate that ACA+ SSc patients have an enhanced risk of macrovascular injury as well. This group should be followed closely and modifiable cardiovascular risk factors should be treated at an early stage.

Introduction

Systemic sclerosis (SSc) is an autoimmune rheumatic disease characterized by fibrosis of the skin, microvasculopathy and involvement of internal organs. Patients with SSc have a shortened lifespan mainly due to heart and lung manifestations.^[1] In other autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) the occurrence of premature cardiovascular morbidity and subclinical atherosclerosis has been well documented.^[2,3] Whether ischemic macrovascular disease and/or accelerated atherosclerosis also are features of SSc is unclear. Most previous studies are fairly small and results contradictive,^[4–6] however, a recent meta-analysis concluded that carotid intima-media thickness (IMT) was greater in SSc patients than in controls.^[7]

The pathogenesis of SSc is unknown, but activation of B cells results in the production of antinuclear antibodies (ANA) in 90% of patients. The ANA specificities most commonly demonstrated in SSc; anticentromere (ACA) and antitopoisomerase 1 (ATA) antibodies, characterize two different clinical SSc subsets. In limited cutaneous scleroderma (lcSSc, 80% of SSc) the occurrence of ACA is common^[8] and Raynaud's phenomena may precede fibrotic skin by several years.^[1] Diffuse cutaneous systemic sclerosis (dcSSc) is less common, associated with ATA, and an extensive skin involvement and pulmonary fibrosis often parallel or may even precede Raynaud's phenomena.

In this study, we investigated the prevalence of ischemic arterial events and measures of atherosclerosis in patients with SSc and in controls from the general population. Traditional cardiovascular risk factors were tabulated. Since both atherosclerosis and cardiovascular disease are known to be associated with systemic inflammation, we also investigated the distribution of a large set of inflammatory and endothelial biomarkers.

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Arthritis Res Ther. 2013;15(4) © 2013 BioMed Central, Ltd.
Copyright to this article is held by the author(s), licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original citation.

Abstract and Introduction
Methods
Results
Discussion
Conclusions
References

Table 1. Characteristics of systemic sclerosis patients and controls at inclusion.
	Patients (n = 111)	Controls (n = 105)	P value
Age, years	61.8 ± 12.5	61.5 ± 12.3	ns
Gender female % (n)	81 (90)	86 (90)	ns
Disease characteristics
Disease duration (years)	9.4 (5.6–17.4)	-	-
Diffuse cutaneous % (n) Limited cutaneous % (n)	22 (24) 78 (87)	- -	-
Pulmonary fibrosis % (n)	46 (51)	-	-
Suspected pulmonary hypertension % (n)	15 (17)	0	-
Raynaud % (n)	95 (105)	11 (12)	-
Digital ulcers ever % (n)	39 (43)	0	-
Calcinosis % (n)	27 (30)	0	-
Myositis % (n)	9 (10)	0	-
Arthritis % (n)	29 (32)	4 (4)	-
Kidney involvement % (n)	7 (8)	0	-
Skin score	6 (3–10)	0	-
Disease activity	0.5 (0–2)	-	-
Disease severity	5 (3–6)	-	-
Autoantibodies Anticentromere (ACA) % (n) Antitopoisomerase 1 (ATA) % (n) Antinuclear (ANA) neg % (n)	32 (35) 23 (25) 7 (8)	- - -
Traditional cardiovascular risk factors
Body mass index (kg/m²)	24.2 ± 3.80	26.0 ± 3.7	0.0005
Waist-hip ratio	0.83 ± 0.09	0.84 ± 0.08	ns
Ever smoked % (n) Current smoker % (n)	53 (59) 11 (12)	44 (46) 7 (7)	ns ns
Systolic BP (mmHg) Diastolic BP (mmHg) Hypertension % (n)	123.18 ± 17.94 71.63 ± 10.65 30 (33)	124.09 ± 18.59 74.5 ± 9.49 20 (21)	ns 0.04 ns
P-glucose (mmol/l) Diabetes % (n)	5.45 ± 1.17 6 (7)	5.43 ± 1.34 7 (7)	ns ns
Cholesterol (mmol/l) LDL (mmol/l) HDL (mmol/l) Triglycerides (mmol/l)	5.20 ± 1.04 3.32 ± 0.93 1.3 (1.0–1.5) 0.99 (0.76–1.5)	5.24 ± 1.15 3.37 ± 0.91 1.4 (1.2–1.7) 0.93 (0.67–1.3)	ns ns ns (0.09) 0.03
Inflammatory biomarkers
hsCRP (mg/l)	2.2 (1.0–4.3)	1.75 (0.76–3.2)	0.05
Orosomucoid (g/l)	0.86 ± 0.23	0.77 ± 0.17	0.0009
Alpha1antitrypsine (g/l)	1.5 (1.4–1.6)	1.4 (1.2–1.5)	<0.0001
Fibrinogen (g/l)	3.77 (3.3–4.34)	3.53 (2.80–4.25)	0.03
Sedimentation rate (mm) Interleukin-6 (pg/ml)	14 (9–26) 29.9 (21.4–40.9)	10 (7–16.5) 27.1 (21.2–32.5)	0.002 ns (0.08)
Endothelial biomarkers
VCAM-1 (ng/l)	698 (546–807)	531 (431–719)	<0.0001
ICAM-1 (ng/l)	376 (314–472)	330 (254–450)	0.002
VEGF (pg/ml)	182 (143–258)	156 (103–239)	0.009
vWF (IU/ml)	1.25 (0.90–1.70)	0.85 (0.58–1.36)	<0.0001
Renal function
eGFR (mL/min/1.73 m²)	74 (50–116)	104 (89–126)	0.01

Distributions are given as % (n), median (interquartile range) or mean ± standard deviation. BP, blood pressure; LDL, low-density lipoprotein; HDL, high-density lipoprotein; hsCRP, high-sensitivity C reactive protein; VCAM-1, vascular cell adhesion molecule 1; ICAM-1, intercellular adhesion molecule 1; VEGF, vascular endothelial growth factor; vWF, von Willebrand factor; eGFR, estimated glomerular filtration rate, based on cystatin C measurements.

Table 2. Ischemic arterial events and surrogate measures of atherosclerosis in systemic sclerosis patients versus controls.
	Patients (n = 111)	Controls (n = 105)	Odds ratio (95% CI)	P value
Any arterial event % (n)	18 (20)	7 (7)	3.1 (1.2–7.6)	0.01
IHD % (n)	12 (13)	4 (4)	3.3 (1.1–10.6)	0.03
ICVD % (n)	3 (4)	3 (3)	0.9 (0.2–4.7)	ns
IPVD % (n)	8 (9)	1 (1)	9.2 (1.1–73.7)	0.02
Plaques % (n)	48 (52)	41 (43)	1.3 (0.7–2.3)	ns
			β-coefficient
IMT mm	0.68 ± 0.13	0.68 ± 0.13	-0.02	ns
ABI	1.13 (1.1–1.2)	1.12 (1.1–1.2)	-0.08	ns

Any arterial event refers to any ischemic arterial event, including IHD, ICVD and IPVD. IHD, ischemic heart disease; ICVD, ischemic cerebrovascular disease; IPVD, ischemic peripheral vascular disease; IMT, intima-media thickness; ABI, ankle-brachial index.

Table 3. Variables associated with ischemic arterial events in systemic sclerosis patients after age adjustment.
	Any event (n = 20)		IHD (n = 13)		IPVD (n = 9)
	Odds ratio (95% CI)	P value	Odds ratio (95% CI)	P value	Odds ratio (95% CI)	P value
Age	1.10 (1.05–1.17)	<0.0001	1.06 (1.01–1.13)	0.02	1.13 (1.05–1.26)	0.0005
Associations after adjustment for age
Kidney disease	8.8 (1.5–55.8)	0.01	6.6 (1.12–36.15)	0.04	ND	0.3
Skin score	1.13 (1.03–1.24)	0.008	1.07 (0.97–1.18)	0.1	1.16 (1.02–1.32)	0.02
Disease severity	1.29 (1.05–1.62)	0.02	1.11 (0.88–1.39)	0.4	1.15 (0.85–1.55)	0.3
ACA+	3.61 (1.21–11.3)	0.02	1.9 (0.55–6.45)	0.2	6.8 (1.37–45.3)	0.02
ATA+	0.18 (0.01–1.01)	0.05	0.00003 (0–0.6)	0.01	0.83 (0.04–5.67)	0.9
VCAM-1	5.30 (0.51–62.1)	0.2	27.3 (2.52–427. 4)	0.005	0.37 (0.02–5.46)	0.2
VEGF	0.68 (0.24–1.84)	0.4	0.29 (0.09–0.93)	0.03	0.52 (0.12–2.33)	0.4
eGFR	0.26 (0.10–0.62)	0.003	0.32 (0.12–0.81)	0.02	0.57 (0.15–3.65)	0.5

IHD, ischemic heart disease; IPVD, ischemic peripheral vascular disease; CI, confidence interval; ACA, anticentromere antibody; +, positivity; ATA, antitopoisomerase 1 antibody; VCAM-1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor; eGFR, estimated glomerular filtration rate, based on cystatin C measurements.

Table 4. Variables associated with measures of atherosclerosis in systemic sclerosis patients after age adjustment.
	Plaques (n = 52)		IMT		ABI
	Odds ratio (95% CI)	P value	β-coefficient	P value	β-coefficient	P value
Age	1.09 (1.05–1.14)	<0.0001	0.66	<0.0001	-0.20	0.03
Associations after adjustment for age
Gender female	0.39 (0.12–1.18)	0.1	-0.19	0.0001	-0.12	0.2
ACA+	2.9 (1.2–7.5)	0.02	-0.01	0.9	-0.14	0.2
Digital ulcers	2.6 (1.1–6.6)	0.03	0.10	0.2	-0.09	0.4
Kidney disease	11.5 (1.7–232)	0.03	-0.05	0.5	0.05	0.6
Disease activity	1.6 (1.04–2.5)	0.03	0.10	0.2	-0.34	0.0004
Disease severity	1.3 (1.1–1.5)	0.005	0.12	0.1	0.13	0.2
Waist-hip ratio	2.6 (0.01–645)	0.7	0.09	0.2	0.19	0.04
Ever smoked	2.5 (1.05–6.7)	0.04	0.10	0.2	0.24	0.01
Systolic BP	1.0 (1.0–1.1)	0.02	0.28	0.0008	-0.06	0.6
Diastolic BP	1.1 (1.0–1.1)	0.008	0.13	0.1	-0.02	0.9
Interleukin-6	3.5 (1.5–9.3)	0.003	0.12	0.1	-0.13	0.2
VCAM-1	9.4 (1.8–58.3)	0.008	-0.05	0.5	0.03	0.8
ICAM-1	0.32 (0.05–1.98)	0.2	0.16	0.04	-0.12	0.2
eGFR	0.4 (0.2–0.99)	0.04	0.11	0.2	-0.04	0.7

IMT, intima-media thickness; ABI, ankle-brachial index; CI, confidence interval; ACA, anticentromere antibodies; +, positivity; BP, blood pressure; VCAM-1, vascular cell adhesion molecule 1; ICAM-1, intercellular adhesion molecule 1; eGFR, estimated glomerular filtration rate, based on cystatin C measurements.

Table 5. Multivariable adjusted model for occurrence of carotid plaques.
	Plaques
Functional groups and included variables	Odds ratio (95% CI)	P value
Age	1.1 (1.03–1.16)	0.003
Disease characteristics
ACA+	4.0 (1.26–14.1)	0.02
Traditional risk factors
Diastolic blood pressure (mmHg)	1.1 (1.01–1.11)	0.04
Inflammatory biomarkers
IL-6 (pg/ml)	3.8 (1.3–13.3)	0.01
Endothelial biomarkers
VCAM-1 (ng/ml)	1.5 (0.15–14.7)	0.7
Kidney function test
eGFR (mL/min/1.73 m²)	0.3 (0.04–1.07)	0.07

CI, confidence interval; ACA, anticentromere antibodies; +, positivity; IL, interleukin; VCAM-1, vascular cell adhesion molecule 1; eGFR, estimated glomerular filtration rate, based on cystatin C measurements.

Table 6. Ischemic arterial events and surrogate measures of atherosclerosis in ACA+ patients versus ACA-patients and controls.
	Occurrence of events and atherosclerosis			ACA+ vs. ACA-		ACA+ vs. controls
	ACA+ (n = 34)	ACA-(n = 77)	Controls (n = 105)	Odds ratio** (95% CI)	P value**	Odds ratio* (95% CI)	P value*
Any arterial event % (n)	32 (11)	11 (9)	7 (7)	5.1 (1.57–18.6)	0.01	8.5 (2.6–31.7)	0.0003
IHD % (n)	18 (6)	9 (7)	4 (4)	2.6 (0.7–10.0)	0.2	4.8 (1.2–20.7)	0.02
ICVD % (n)	6 (2)	3 (2)	3 (3)	4.0 (0.4–49.0)	0.2	2.0 (0.2–13.9)	0.6
IPVD % (n)	18 (6)	4 (3)	1 (1)	9.1 (1.6–79.1)	0.01	70.1 (6.5–2524)	<0.0001
Plaque % (n)	65 (22)	39 (30)	41 (43)	3.1(1.2–8.5)	0.02	2.8 (1.1–7.6)	0.04
				β-coefficient		β-coefficient
IMT mm	0.69 ± 0.13	0.68 ± 0.13	0.68 ± 0.13	0.03	0.7	0.01	0.6
ABI	1.1(1.03–1.2)	1.1 (1.17–1.2)	1.1 (1.07–1.2)	-0.12	0.08	-0.14	0.07

Distributions are given as %, median (interquartile range) or mean ± standard deviation. **adjusted for age, sex and disease duration; *adjusted for age and sex. ACA, anticentromere antibodies; +, positivity; -, negativity; CI, confidence interval; IHD, ischemic heart disease; ICVD, ischemic cerebrovascular disease; IPVD, ischemic peripheral vascular disease; IMT, intima-media thickness; ABI, ankle-brachial index.