Summary
Increased production of autoantibodies is a characteristic feature of systemic lupus erythematosus (SLE) and there is evidence that several of these autoantibodies may contribute to increased ...cardiovascular disease (CVD) in SLE. Autoantibodies against the apolipoprotein (apo) B‐100 peptides p45 and p210 have been associated with a lower CVD risk in non‐SLE cohorts. The aim of the present study was to investigate how SLE affects the occurrence of these potentially protective autoantibodies. The study cohort consisted of 434 SLE patients and 322 age‐ and sex‐matched population controls. Antibodies against native and malondialdehyde (MDA)‐modified p45 and p210 were measured by enzyme‐linked immunosorbent assay (ELISA). SLE patients had significantly lower levels of p210 immunoglobulin (Ig)G and p45 IgM (both the native and malondialdehyde (MDA)‐modified forms). SLE patients with manifest CVD (myocardial infarction, ischaemic cerebrovascular disease or peripheral vascular disease) had lower levels p210 IgG and p45 IgM than SLE patients without CVD. Decreased levels of these autoantibodies were also observed in SLE patients with permanent organ damage, as assessed by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) Damage Index (SDI). The present findings show that patients with SLE, a condition generally characterized by abundance of autoantibodies of multiple specificities, have reduced levels of antibodies against the apo B‐100 antigens p45 and p210 and that the levels of these antibodies are reduced further in SLE patients with CVD. These observations suggest the possibility that an impaired antibody‐mediated removal of damaged LDL particles may contribute to the development of vascular complications and organ damage in SLE.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Cardiovascular disease (CVD) is overrepresented in patients with systemic lupus erythematosus (SLE). We determined the prevalence of traditional and nontraditional risk factors for CVD in SLE ...patients with and without CVD compared with controls.
Twenty-six women (aged 52+/-8.2 years) with SLE and a history of CVD (SLE cases) were compared with 26 age-matched women with SLE but without manifest CVD (SLE controls) and 26 age-matched population-based control women (population controls). Common carotid intima-media thickness (IMT) was measured by B-mode ultrasound as a surrogate measure of atherosclerosis. SLE cases had increased IMT compared with SLE controls (P=0.03) and population controls (P=0.001), whereas IMT of SLE controls did not differ from population controls. SLE cases had raised plasma concentrations of circulating oxidized LDL (OxLDL; P=0.03), as measured by the monoclonal antibody EO6, and autoantibodies to epitopes of OxLDL (P<0.001); dyslipidemia with raised triglycerides (P<0.001) and lipoprotein(a) (P=0.002) and decreased HDL-cholesterol concentrations (P=0.03); raised alpha-1-antitrypsin (P=0.002), lupus anticoagulant (P=0.007), and homocysteine levels (P=0.03); more frequent osteoporosis (P=0.03); and a higher cumulative prednisolone dose (P=0.05) compared with SLE controls. Disease duration, smoking, blood pressure, body mass index, and diabetes mellitus did not differ significantly between the groups.
alpha set of distinct CVD risk factors separate SLE cases from SLE controls and population controls. If confirmed in a prospective study, they could be used to identify SLE patients at high risk for CVD in order to optimize treatment.
An increase in intima-media thickness (IMT) in the common carotid artery (CCA) is commonly used as a marker of atherosclerosis. The purpose of this study was to investigate the relationship between ...IMT in the CCA and atherosclerosis in the carotid bifurcation.
182 consecutive patients (mean age, 67 years) referred for carotid duplex scanning were included. We measured IMT and classified plaques by means of a high-resolution ultrasound technique.
IMT was correlated to age, male gender, ischemic heart disease, and presence of plaques or stenoses in any of the carotid bifurcations. In men, IMT was larger on the left than on the right side. Plaques were seen in 163 carotid bifurcations, in 45 of these with > 50% stenosis. On the left side but not on the right, there was a correlation between IMT in the CCA and presence of plaques or stenoses in the carotid bifurcation. Echogenic plaques were more common than echolucent, but the latter caused significantly more stenoses. No relationship was found between plaque echogenicity and IMT.
IMT of the CCA is correlated to the degree of atherosclerosis in the carotid bifurcations in general and on the left side also to the presence of plaques or stenoses in the left carotid bifurcation. Our results support earlier observations suggesting faster development of carotid atherosclerosis on the left than on the right side. Echogenic plaques were more common and generally smaller than echolucent plaques, but there was no correlation between plaque echogenicity and IMT.
Abstract
Objective
Complement components, including C4d, can be found on activated platelets, a process associated with vascular disease in SLE. We investigated whether platelet C4d (PC4d) adds ...additional value to traditional and known lupus-associated risk factors when identifying SLE patients with vascular disease.
Methods
This cross-sectional study included 308 well-characterized SLE patients and 308 matched general population controls. PC4d deposition was analysed using flow cytometry. Values >95% of controls were considered as PC4d positive (+). aPL were determined by Luminex, and the LA test was performed by DRVVT. History of vascular disease (composite and as separate outcomes) was defined at inclusion.
Results
SLE patients had increased PC4d deposition as compared with population controls (50 vs 5%, P < 0.0001). PC4d+ positively associated with any vascular events, and separately with venous and cerebrovascular events, and also with all investigated aPL profiles. The association for any vascular event remained statistically significant after adjustment for traditional and SLE-associated risk factors (odds ratio: 2.3, 95% CI: 1.3, 4.3, P = 0.008). Compared with patients negative for both PC4d and LA, patients with double positivity were more likely to have vascular disease (odds ratio: 12.3, 95% CI: 5.4, 29.3; attributable proportion due to interaction 0.8, 95% CI: 0.4, 1.1)
Conclusion
PC4d+ is associated with vascular events in SLE, independently of traditional and SLE-associated risk factors. Concurrent presence of PC4d and LA seem to interact to further increase the odds for vascular events. Prospective studies should examine whether the aPL/PC4d combination can improve prediction of vascular events in SLE and/or APS.
Microangiopathy is retarded by improved blood glucose control in patients with IDDM. Whether or not this is true for macroangiopathy (atherosclerosis) has remained unclear. A total of 59 patients (44 ...+/- 1.5 years, previous HbA1C 9.4 +/- 0.2%, mean +/- SE) with IDDM were investigated. Of the 59 patients, 31 had been randomized to long-term intensified conventional insulin treatment (ICT), and the remaining 28 had received standard insulin treatment (ST). Blood glucose control was significantly better in the ICT patients with an HbAlc value (mean of 29 values during 10 years) of 7.1 +/- 0.1% compared with the ST patients' 8.2 +/- 0.2% (P < 0.0001). With high-frequency ultrasound, endothelial function was measured as flow-mediated dilation of the right brachial artery. The carotid arteries were scanned for plaques, intima-media thickness was measured, and arterial wall stiffness was calculated in the right common carotid artery. These measurements correlate with manifest and/or risk factors for coronary atherosclerosis. The patients in the ST group had stiffer arteries (P = 0.011) and thicker intima-media in the left common carotid artery (P = 0.009) than those in the ICT group. Patients with lower HbA1c generally had better endothelial function (P = 0.028) and less stiff arteries (P = 0.009). Better blood glucose control in patients with IDDM is related not only to less microangiopathy but also to a slower development of atherosclerosis.
There is convincing evidence that adaptive immune responses affect the development of atherosclerosis and thrombosis and several autoimmune diseases are associated with increased cardiovascular risk. ...However, our understanding of the underlying mechanisms remains limited. We investigated how biomarkers reflecting four aspects of autoimmunity: apoptosis, inflammation, tissue degradation and repair, associate with cardiovascular disease (CVD) in subjects with systemic lupus erythematosus (SLE).
We investigated 484 well-characterized SLE patients, 69 of whom had CVD (coronary artery disease, cerebrovascular disease or peripheral artery disease), and 253 controls. Occurrence of carotid plaques was investigated with ultrasound. Plasma levels of biomarkers reflecting apoptosis (Fas, TNF receptor 1, TRAIL receptor 2), inflammation (IL-6, IL-8, monocyte chemotactic protein-1), tissue degradation (matrix metalloproteinase (MMP)-1, MMP-3, MMP-7), and tissue repair (platelet-derived growth factor, epidermal growth factor and stem cell factor) were analyzed by Proximity Extension Assay.
Subjects with SLE had markedly elevated plasma levels of biomarkers reflecting apoptosis, inflammation and tissue degradation as compared to controls. SLE patients with CVD had higher levels of Fas, TNF receptor 1, TRAIL receptor 2, MMP-1 and -7 than those without CVD. The same associations were found for the presence of a carotid plaque. When controlling for the factors included in the Framingham risk score, all biomarkers except MMP-1 remained associated with the presence of a carotid plaque, while only TRAIL receptor 2 levels remained significantly associated with CVD.
Our findings argue that the cardiovascular risk in SLE is associated with increased cell death by apoptosis and tissue degradation.
Display omitted
•There is evidence that other mechanisms than LDL-driven inflammation are increasingly important in CVD.•Experimental studies have implicated immune responses in the development of atherosclerosis.•Several autoimmune diseases are associated with increased CVD risk, suggesting that autoimmunity may contribute to CVD.•This study shows that CVD in SLE is associated with elevated levels of biomarkers reflecting apoptosis and tissue degradation.•Tissue injury rather than inflammation may be the cause of cardiovascular complications in autoimmune diseases such SLE.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK, ZRSKP
Aims/hypothesis
We investigated skin microcirculation and its association with HbA
1c
and the incidence of ischaemic foot ulcer in patients with type 1 diabetes formerly randomised (1982–1984) to ...intensified conventional treatment (ICT) or standard treatment (ST) with insulin for a mean of 7.5 years.
Methods
We re-determined the skin microcirculation of 72 patients (ICT 35 vs ST 37) from the original Stockholm Diabetes Intervention Study with iontophoresis topically applied with the following vasoactive stimuli: acetylcholine (ACh) (endothelial-dependent vasodilatation), sodium nitroprusside (SNP) (endothelial-independent vasodilatation), and capsaicin (C-nociceptive-dependent vasodilatation). HbA
1c
levels (mean of 14 values/patient) were prospectively collected between 1990 and 1995 and tested for association with skin microcirculation. The patients were followed until first hospitalisation for an ischaemic foot ulcer or until 2011.
Results
During the median 28 years of follow-up, three patients developed ischaemic foot ulcers in the ICT group compared with ten in the ST group (logrank,
p
= 0.035). At the time of iontophoresis, HbA
1c
was lower in the ICT group (median 57 mmol/mol minimum–maximum 40–79 mmol/mol) compared with the ST group (68 mmol/mol 41–96 mmol/mol,
p
< 0.01) (DCCT: ICT 7.4% 5.8–9.4% vs ST 8.4% 5.9–10.9%). Stimulated blood flow was higher in the ICT vs ST group with significantly increased perfusion units (PU) for: ACh (8.1 PU 4.6–24.7 PU vs 5.3 PU 1.7–21.4 PU,
p
< 0.01); SNP (8.1 PU 2.2–20.1 PU vs 5.6 PU 2.3–19.2 PU,
p
= 0.03); and capsaicin (5.0 PU 1.7–22.9 PU vs 3.4 PU 1.5–8.4 PU,
p
< 0.01). HbA
1c
was associated with vasodilatation induced by ACh (
b
= −0.02,
p
< 0.01) and capsaicin (
b
= −0.02,
p
= 0.03). HbA
1c
was independently associated with ACh (
b
= −1.48,
p
< 0.01) and capsaicin-induced vasodilatation (
b
= −1.45,
p
< 0.01).
Conclusions/interpretation
Improved glycaemic control in patients with type 1 diabetes is associated with an improvement in skin microcirculation and with a lower incidence of ischaemic foot ulcers.
Trial registration:
ClinicalTrials.gov NCT01957930
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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.
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.
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.
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.
Patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) have increased risk of cardiovascular disease (CVD). We investigated whether single nucleotide polymorphisms (SNPs) at ...autoimmunity risk loci were associated with CVD in SLE and RA.
Patients with SLE (n=1045) were genotyped using the 200K Immunochip SNP array (Illumina). The allele frequency was compared between patients with and without different manifestations of CVD. Results were replicated in a second SLE cohort (n=1043) and in an RA cohort (n=824). We analysed publicly available genetic data from general population, performed electrophoretic mobility shift assays and measured cytokine levels and occurrence of antiphospholipid antibodies (aPLs).
We identified two new putative risk loci associated with increased risk for CVD in two SLE populations, which remained after adjustment for traditional CVD risk factors. An
risk allele, rs17581834(T) was associated with stroke/myocardial infarction (MI) in SLE (OR 2.3 (1.5 to 3.4), P=8.5×10
) and RA (OR 2.8 (1.4 to 5.6), P=3.8×10
), meta-analysis (OR 2.5 (2.0 to 2.9), P=3.5×10
), but not in population controls. The
risk allele affected protein binding, and SLE patients with the risk allele had increased levels of plasma-IL10 (P=0.004) and aPL (P=0.01). An
risk allele, rs799454(G) was associated with stroke/transient ischaemic attack in SLE (OR 1.7 (1.3 to 2.2), P=2.5×10
) but not in RA. The
risk allele is an expression quantitative trait locus for four genes.
The
risk allele was associated with stroke/MI in SLE and RA, but not in the general population, indicating that shared immune pathways may be involved in the CVD pathogenesis in inflammatory rheumatic diseases.
Natural IgM autoantibodies have been proposed to convey protection from autoimmune pathogenesis. Herein, we investigated the IgM responses in 396 systemic lupus erythematosus (SLE) patients, divided ...into subgroups based on distinct autoantibody profiles. Depressed IgM levels were more common in SLE than in matched population controls. Strikingly, an autoreactivity profile defined by IgG anti-Ro/La was associated with reduced levels of specific natural IgM targeting phosphorylcholine (PC) antigens and malondialdehyde (MDA) modified-protein, as well as total IgM, while no differences were detected in SLE patients with an autoreactivity profile defined by anti-cardiolipin/β2glycoprotein-I. We also observed an association of reduced IgM levels with the HLA-DRB1*03 allelic variant among SLE patients and controls. Associations of low IgM anti-PC with cardiovascular disease were primarily found in patients without antiphospholipid antibodies. These studies further highlight the clinical relevance of depressed IgM. Our results suggest that low IgM levels in SLE patients reflect immunological and genetic differences between SLE subgroups.
•Low IgM levels are more common in SLE patients than in controls.•Patients with anti-Ro/La autoimmunity often have strikingly decreased IgM levels.•Low IgM was seen for specific IgM anti-PC, anti-MDA, anti-CWPS, as well as total IgM.•Low natural IgM may be associated to HLA-DRB1*03 in both SLE and controls.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
PDF
