Systemic Lupus Erythematosus (SLE) is an autoimmune, inflammatory disease that mainly affects
women. The prognosis of SLE has improved dramatically, but mortality rates are still higher than in the
general population. With the improved general prognosis, cardiovascular disease (CVD) has emerged as a
major cause of morbidity and mortality among SLE patients. Previous studies have demonstrated that the
development of atherosclerosis is accelerated in SLE, and have identified a set of traditional and nontraditional
risk factors that characterize SLE patients with CVD. Nevertheless, many unsolved issues with
respect to SLE related CVD remain. The general aim of this thesis was to investigate risk factors for
manifest CVD and for cardiovascular mortality (CVM) in SLE, with special focus on traditional risk
factors, lupus phenotype, inflammatory and endothelial biomarkers, autoantibodies and genetic
predisposition.
In the first paper, we prospectively studied traditional and non-traditional risk factors for
the development of the first cardiovascular event (CVE) in 182 SLE patients with a follow-up time of 8
years. 24(13%) patients had a first event. We demonstrated that of the traditional risk factors, only age
and smoking predicted the first CVE. Additionally, antiphospholipid antibodies (aPL), endothelial
biomarkers, represented by soluble vascular cell adhesion molecule 1(sVCAM-1), and absence of
thrombocytopenia were independent predictors of CVE. Thus, activation of the endothelium and the
coagulation system are important features in SLE-related CVD and the importance to advocate smoking
cessation among SLE patients is underscored
In the second paper, we prospectively investigated causes of mortality and risk factors for
overall mortality and CVM in a cohort of 208 SLE patients, with a follow-up time of 12 years. We also
evaluated Systematic coronary risk evaluation (SCORE, tool for evaluating the 10 year risk for
cardiovascular death in the age span 40-65 years, based on traditional risk factors) in this population.
Cystatin C, a sensitive measure of renal function, in addition to traditional and non-traditional risk
factors, were evaluated as risk factors. 42 patients died, 48 % of which were due to CVM. Age, previous
arterial events and high cystatin C levels were the strongest predictors for overall mortality and for CVM.
After adjusting for these three variables, smoking, sVCAM-1 and high sensitiviy C-reactive protein
(hsCRP) predicted CVM. SCORE estimated 4 but we observed 9 cases of CVM, a non-significant
difference. We conclude that except for smoking, traditional risk factors are less important than cystatin
C, endothelial and inflammatory biomarkers as predictors of CVM in SLE patients.
In the third paper, we investigated whether a risk allele for SLE in the signal transducer
and activator of transcription factor 4 gene (STAT4) was associated with vascular events or presence of
antiphospholipid antibodies (aPL). A total of 578 unrelated SLE patients (424 from mid-Sweden and 154
from southern-Sweden) were included in a cross-sectional design. Occurrence of previous cardiovascular
events and aPL were tabulated. Matched controls (N=651) were genotyped as a comparison. The results
demonstrate that the STAT4 risk allele was associated with ischemic cerebrovascular disease (ICVD),
with a dose-dependent relationship between ICVD and number of risk alleles. The risk allele was
furthermore associated with the presence of two or more aPLs, also in a dose-dependent manner. The
association remained after adjustment for known traditional risk factors. We conclude that patients with
the STAT4 risk allele have an increased risk of ICVD. Our results imply that genetic predisposition is an
important risk factor for ICVD in SLE patients, and that aPL may be one underlying mechanism.
In the fourth paper, we evaluated the potential association between smoking and aPL. 367
SLE patients were investigated in a cross-sectional study. Occurrence of aPL (anticardiolipin (aCL) IgG
and IgM, anti-β2 glycoprotein-1 IgG (aβ2GP1 IgG), lupus anticoagulant (LAC)) and smoking habits
(never, ever, former, current) were tabulated. Never smoking was used as reference in all calculations. In
multivariable models, adjusted for age, sex and age at disease onset, aCL and aβ2GP1 of the IgG isotype
and LAC were associated with ever smoking, this association seemed to be driven mainly by the former
smoking group. Our results demonstrate that smoking is associated with pro-thrombotic aPL in SLE
patients, though we can not from this study draw firm conclusions about the temporal relationship
between exposure to smoking and occurrence of aPL. Further studies are warranted to investigate the
mechanisms behind these observations.
In prospective studies we have demonstrated that in particular smoking, systemic
inflammation, endothelial activation and aPL are major risk factors for SLE related CVD and CVM.
Furthermore, genetic predisposition, in our studies represented by a STAT4 SLE risk allele, contributes to
the high risk of ICVD and to the occurrence of aPL, a possible underlying pathogenic mechanism. Finally
we demonstrate that smoking, known to have unfavorable effects on the immune system and to
significantly increase cardiovascular risk in SLE patients, is also associated with pro-thrombotic aPL in
patients with SLE. Thus in SLE smoking stands out as the most important of the traditional risk factors
with potential influence also on lupus related risk factors such as aPL