Systemic Low-Grade Inflammation and Cardiovascular Disease in Systemic Lupus Erythematosus: Reply

AbstractSystemic lupus erythematosus (SLE) is a potentially fatal complex autoimmune disease, that is characterized by widespread inflammation manifesting tissue damage and comorbidities across the human body including heart, blood vessels, joints, skin, liver, kidneys, and periodontal tissues. The etiology of SLE is partially attributed to a deregulated inflammatory response to microbial dysbiosis and environmental changes. In the mouth, periodontal environment provides an optimal niche to assay local dynamic microbial ecological changes in health and disease important to systemic inflammation in SLE subjects. Our aim was to evaluate the reciprocal impact of periodontal subgingival microbiota on SLE systemic inflammation. Ninety-one female subjects were recruited, including healthy (n=31), SLE-inactive (n=29), and SLE-active (n=31). Patients were screened for probing depth (PD), bleeding on probing (BOP), clinical attachment level (CAL), and classified with or without periodontal dysbiosis, periodontitis. Serum inflammatory cytokines were measured by human cytokine panel and subgingival biofilm was examined by DNA-DNA checkerboard. The results showed significant upregulation of proinflammatory cytokines in individuals with SLE when compared to controls. Stratification of subject’s into SLE-inactive (I) and SLE-active (A) phenotypes or periodontitis and non-periodontitis groups provided new insights into SLE pathophysiology. While low-grade inflammation was found in SLE-I subjects, a potent anti-inflammatory cytokine, IL-10 was found to control clinical phenotypes. Out of twenty-four significant differential oral microbial abundances found in SLE, fourteen unique subgingival bacteria profiles were found to be elevated in SLE. Pathogens from periodontal disease sites (Treponema denticola and Tannerella forsythia) showed increase abundance in SLE-A subjects when compared to controls. Cytokine-microbial correlations showed that periodontal pathogens dominating the environment increased proinflammatory cytokines systemically. Deeper clinical attachment loss and periodontal pathogens were found in SLE subjects, especially on SLE-I, likely due to long-term chronic and low-grade inflammation. Altogether, local periodontal pathogen enrichment was positively associated with high systemic inflammatory profiles, relevant to the overall health and SLE disease pathogenesis.

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Association of Resting Heart Rate With Arterial Stiffness and Low-Grade Inflammation in Women With Systemic Lupus Erythematosus

Angiology ◽

10.1177/0003319717746525 ◽

2017 ◽

Vol 69 (8) ◽

pp. 672-676 ◽

Cited By ~ 3

Author(s):

José Antonio Vargas-Hitos ◽

Alberto Soriano-Maldonado ◽

Josefa Martínez-Bordonado ◽

Isabel Sánchez-Berná ◽

Daniel Fernández-Bergés ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Heart Rate ◽

Arterial Stiffness ◽

Lupus Erythematosus ◽

Low Grade ◽

Model Assessment ◽

Resting Heart Rate ◽

Systemic Lupus ◽

Cross Sectional ◽

Low Grade Inflammation

Resting heart rate (RHR) is associated with arterial stiffness, inflammation, and cardiovascular (CV) and all-cause mortality in the general population and in patients at high CV risk. We assessed the association of RHR with arterial stiffness and low-grade inflammation (LGI) in a cross-sectional study that included 101 women with systemic lupus erythematosus (SLE) without a history of CV disease or arrhythmia or who were under treatment that may cause bradycardia. Pulse wave velocity (PWV; a measure of arterial stiffness), RHR, and markers of LGI (ie, C-reactive protein, fibrinogen, erythrocyte sedimentation rate, insulin, and homeostatic model assessment index) were measured. The patients with the highest RHR (quartile 4; mean RHR = 87.2 bpm) had a PWV 0.61 m/s (95% confidence interval [CI]: 0.08-1.14; P = .024) greater than patients with the lowest RHR (quartile 1; RHR = 63.0 bpm), independent of age, systolic blood pressure, disease activity, smoking, and being physically inactive. Similarly, patients with the highest RHR (quartile 4) showed a significantly less favorable clustered LGI index than patients in quartile 1 ( b = .58; 95% CI: 0.212-0.948; P = .002). Higher RHR is associated with greater arterial stiffness and LGI in women with SLE. Further research to determine the prognostic value of RHR in this population is warranted.

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Abstract 16069: Low-Density Lipoprotein of Systemic Lupus Erythematosus Patients Contains Lysophosphatidylcholine-Rich Lipid That Induces Overexpression of CX3CL1 in Endothelial Cells

Circulation ◽

10.1161/circ.130.suppl_2.16069 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Hua-Chen Chan ◽

Liang-Yin Ke ◽

Hsiu-Chuan Chan ◽

Hung Su ◽

An-Sheng Lee ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Cardiovascular Disease ◽

Endothelial Cells ◽

Lupus Erythematosus ◽

Low Density Lipoprotein ◽

Chemical Properties ◽

Density Lipoprotein ◽

Anion Exchange Chromatography ◽

Exchange Chromatography ◽

Systemic Lupus

Background: Patients with systemic lupus erythematosus (SLE) are twice more likely to develop cardiovascular disease than the general population, even though their plasma LDL cholesterol (LDL-C) levels are usually not elevated. To delineate the mechanisms, we examined the chemical properties of their LDL. Methods and Results: LDL isolated from SLE patients (LDL-C, 105±33 mg/dL; n=24) exhibited greater mobility in agarose gel electrophoresis than LDL of healthy control subjects (LDL-C, 121±25 mg/dL; n=24), secondary to an increased distribution of L5 (2.30±1.3% vs. 0.7±0.3%; P <0.0001), the most electronegative subfraction of LDL identified by anion-exchange chromatography, in total LDL. CX3CL1 is a membrane-bound chemokine expressed in injured endothelial cells (ECs). CD16 + monocytes are CX3CR1-expressing cells that recognize CX3CL1. Compared with control, SLE patients had a twofold ( P <0.001) increase in CX3CL1 and a threefold ( P <0.0001) increase in CD16 + monocytes in the plasma. Moreover, there was a positive correlation between the CX3CL1 and L5 levels (R=0.45; P <0.018). MALDI/TOF mass spectrometry of the lipid extracted from SLE-LDL revealed a shift from phosphatidylcholines (PCs) to lyso-PCs (LPCs), including m/ z 496.33, 524.36, 537.01, 550.94, when compared with the lipid of control LDL (Figure). The shift was especially prominent in L5. Exposing human aortic ECs to L5 but not normal LDL resulted in a fivefold ( P <0.0001) increase in CX3CL1 expression with concomitant apoptosis. These effects of L5 were significantly attenuated by blocking the platelet-activating receptor, confirming the role of phospholipids in L5’s bioactivity. Conclusions: The increased distribution of LPC-rich electronegative LDL, which induces CX3CL1-CX3CR1 interactions between vascular cells, may contribute to the increased cardiovascular disease prevalence in SLE in the absence of LDL-C elevation.

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25-Hydroxyvitamin D and Cardiovascular Disease in Patients With Systemic Lupus Erythematosus: Data From a Large International Inception Cohort

Arthritis Care & Research ◽

10.1002/acr.22291 ◽

2014 ◽

Vol 66 (8) ◽

pp. 1167-1176 ◽

Cited By ~ 39

Author(s):

Apinya Lertratanakul ◽

Peggy Wu ◽

Alan Dyer ◽

Murray Urowitz ◽

Dafna Gladman ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Cardiovascular Disease ◽

Lupus Erythematosus ◽

Inception Cohort ◽

Systemic Lupus ◽

Hydroxyvitamin D ◽

25 Hydroxyvitamin D

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Novel gene variants associated with cardiovascular disease in systemic lupus erythematosus and rheumatoid arthritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2017-212614 ◽

2018 ◽

Vol 77 (7) ◽

pp. 1063-1069 ◽

Cited By ~ 8

Author(s):

Dag Leonard ◽

Elisabet Svenungsson ◽

Johanna Dahlqvist ◽

Andrei Alexsson ◽

Lisbeth Ärlestig ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Systemic Lupus Erythematosus ◽

Cardiovascular Disease ◽

General Population ◽

Lupus Erythematosus ◽

Risk Allele ◽

Snp Array ◽

Inflammatory Rheumatic Diseases ◽

Systemic Lupus ◽

Increased Risk

ObjectivesPatients 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.MethodsPatients 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).ResultsWe 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 IL19 risk allele, rs17581834(T) was associated with stroke/myocardial infarction (MI) in SLE (OR 2.3 (1.5 to 3.4), P=8.5×10−5) and RA (OR 2.8 (1.4 to 5.6), P=3.8×10−3), meta-analysis (OR 2.5 (2.0 to 2.9), P=3.5×10−7), but not in population controls. The IL19 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 SRP54-AS1 risk allele, rs799454(G) was associated with stroke/transient ischaemic attack in SLE (OR 1.7 (1.3 to 2.2), P=2.5×10−5) but not in RA. The SRP54-AS1 risk allele is an expression quantitative trait locus for four genes.ConclusionsThe IL19 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.

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Abstract 05: Race and Hospitalization for Cardiovascular Disease in Patients With Systemic Lupus Erythematosus

Circulation ◽

10.1161/circ.141.suppl_1.05 ◽

2020 ◽

Vol 141 (Suppl_1) ◽

Cited By ~ 1

Author(s):

Meghan Angley ◽

Tene T Lewis ◽

Penelope P Howards ◽

Sung Lim

Keyword(s):

Systemic Lupus Erythematosus ◽

Cardiovascular Disease ◽

African Americans ◽

Lupus Erythematosus ◽

Survival Curve ◽

Population Based ◽

Systemic Lupus ◽

Time To Event Data ◽

Artery Disease ◽

Stratified Analysis

Background: Patients diagnosed with systemic lupus erythematosus (SLE) are at greater risk of cardiovascular disease (CVD) and death at earlier ages than the general population, with African Americans (AA) at risk at earlier ages than non-AAs. However, the association between race and recurrent hospitalizations for CVD, which are associated with mortality, has not been explored. Methods: The Georgia Lupus Registry (GLR) is a population-based registry of individuals with SLE in 2002-2004 in Atlanta, Georgia. Both incident and prevalent cases were enrolled, and we included all cases diagnosed beginning in 2000. The GLR was matched to Georgia inpatient hospital discharge records from 2000-2013. Using ICD-9-CM codes, we identified hospitalizations classified as having coronary heart disease, peripheral artery disease, cerebrovascular disease or heart failure. The Prentice-Williams-Peterson Model with a total time scale measured from diagnosis was used to examine recurrent time to event data. We truncated the number of hospitalizations at 3 to maintain stable modeling estimates. Patients were censored at the time of death or at the end of 2013. Models were adjusted for sex and age at diagnosis. Results: A total of 556 participants in the GLR (87% female, 73% AA) had a median age at SLE diagnosis of 38 years and 27% experienced at least 1 CVD hospitalization, while 17% experienced ≥ 2. Overall, AA race was associated with recurrent hospitalizations (adjusted hazard ratio [aHR]: 1.7, 95% confidence interval [CI]: 1.2, 2.3). In an event-specific stratified analysis, the association between AA race and the hazard of recurrence became even more pronounced in later events (Event 1 aHR: 1.2, 95% CI: 1.0, 1.5; Event 2 aHR: 1.5, 95% CI: 1.2, 2.2; Event 3 aHR: 1.9, 95% CI: 1.1, 3.2). Conclusions: African-Americans with SLE were more likely to experience recurrent hospitalizations for CVD than their non-AA counterparts, suggesting that AA individuals with SLE may be more vulnerable to CV complications of SLE. Figure 1. Survival curve for 1st event

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