Cardiovascular disease biomarkers across autoimmune diseases Joseph Ahearn, Kelly J. Shields, Chau-Ching Liu, Susan Manzi PII: DOI: Reference:
S1521-6616(15)00220-X doi: 10.1016/j.clim.2015.05.024 YCLIM 7515
To appear in:
Clinical Immunology
Received date: Accepted date:
26 April 2015 13 May 2015
Please cite this article as: Joseph Ahearn, Kelly J. Shields, Chau-Ching Liu, Susan Manzi, Cardiovascular disease biomarkers across autoimmune diseases, Clinical Immunology (2015), doi: 10.1016/j.clim.2015.05.024
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TITLE: Cardiovascular disease biomarkers across autoimmune diseases
Authors, Affiliations, and Email addresses:
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Joseph Ahearn, MD, Kelly J. Shields, PhD, Chau-Ching Liu, MD, PhD, Susan Manzi,
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MD, MPH Lupus Center of Excellence
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Autoimmunity Institute
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Corresponding author:
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Allegheny Health Network
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Department of Medicine
Joseph M. Ahearn, MD Allegheny Health Network Pittsburgh, PA 15212 [email protected]
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ABSTRACT:
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Cardiovascular disease is increasingly recognized a major cause of premature mortality
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among those with autoimmune disorders. There is an urgent need to identify those patients with autoimmune disease who are at risk for CVD so as to optimize therapeutic
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intervention and ultimately prevention. Accurate identification, monitoring and
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stratification of such patients will depend upon a panel of biomarkers of cardiovascular disease. This review will discuss some of the most recent biomarkers of cardiovascular
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diseases in autoimmune disease, including lipid oxidation, imaging biomarkers to characterize coronary calcium, plaque, and intima media thickness, biomarkers of
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inflammation and activated complement, genetic markers, endothelial biomarkers, and antiphospholipid antibodies. Clinical implementation of these biomarkers will not only
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enhance patient care but also likely accelerate the pharmaceutical pipeline for targeted intervention to reduce or eliminate cardiovascular disease in the setting of autoimmunity.
KEYWORDS: autoimmune, lupus, rheumatoid, atherosclerosis, biomarkers, cardiovascular
ABBREVIATIONS1
ACKNOWLEDGEMENTS
1 Abbreviations: CB-CAPs - cell-bound complement activation products, EPCs - endothelial progenitor cells, IRF –
interferon regulatory factor, LN – lupus nephritis, NT-proBNP – neurohormone NT-pro brain naturetic protein, piHDL – pro-inflammatory high density lipoprotein, PON3 - paraoxanase-3, PVAT – perivascular adipose tissue, SE – shared epitope
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ACCEPTED MANUSCRIPT 3 We would like to acknowledge Rebecca J. Palmer, PhD for her assistance in the
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preparation of this manuscript.
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1.0 Cardiovascular Diseases in Autoimmunity
Myriad abnormalities of the cardiovascular system have been thoroughly
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described throughout the broad spectrum of autoimmune diseases. Among these, the
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single most common cause of premature mortality in rheumatic conditions is cardiovascular disease in the form of accelerated atherosclerosis [1]. This phenomenon
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was first described in the mid 1990’s in studies of patients with systemic lupus erythematosus (SLE). More recently, similar observations have been made in patients
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with rheumatoid arthritis, psoriatic arthritis, Sjögren’s Syndrome and other rheumatic and autoimmune conditions. Many traditional and non-traditional risk factors are thought to
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contribute to this premature development of cardiovascular disease (CVD) in the context of autoimmunity, including factors such as inflammation, immune system dysfunction, lipoproteins levels, hypertension, insulin resistance, obesity, complement deposition on platelets, irregularities in endothelial progenitor cells, vitamin D deficiencies, and more [1]. Recent evidence suggests that a combination of infection and autoimmunity may promote vascular inflammation and dysfunction in endothelial cells, which accelerates the pathogenesis of CVD in these individuals. There is an urgent need to identify risk factors for CVD in patients with autoimmune diseases. This will facilitate targeted intervention, prevention, and ultimately decrease or eliminate the high risk of morbidity and mortality due to CVD in these patient populations. This review will discuss some of
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ACCEPTED MANUSCRIPT 4 the most promising areas of investigation in efforts to identify and validate biomarkers to aid in these efforts.
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2.0 The Nature and Importance of Biomarkers
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A biomarker is defined as a qualitatively or quantitatively measureable molecule, gene, biochemical, biological event, or imaging event that, when altered, may be
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correlated with a disease pathogenesis/manifestation [2, 3]. As such, biomarkers are
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objective signs, as opposed to subjective symptoms, of illness [3]. Biomarkers are of supreme importance in autoimmune disease because of the inherent complexity of
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diagnosis, monitoring, and predicting outcomes of these multifaceted diseases, which rely upon the accurate interpretation of numerous clinical and laboratory measurements of
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multiorgan system pathology [2]. In addition to their importance in patient care, biomarkers are also critical in the drug discovery and approval process. Currently, the
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pharmaceutical pipeline is slowed by clinical endpoints that may be subjective, infrequent, invasive, otherwise unfeasible, and therefore unreliable, assessments of drug candidates [3]. The establishment of standardized biomarkers promises to improve the evaluations of drug candidates as well as better identify patients most likely to respond to them [3, 4]. As the number of identified autoimmune diseases, the number of affected patients, and the annual costs of treating these illnesses continue to escalate, the need for reliable biomarkers of autoimmune disease increases. The search for biomarkers of autoimmune diseases may be no more pressing than in the area of CVD because of the increasingly recognized influence of accelerated atherosclerosis in morbidity and mortality among patients with SLE, RA and beyond. 3.0 Biomarkers in CVD Manifestations of Systemic Lupus Erythematosus
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ACCEPTED MANUSCRIPT 5 Autoimmune diseases are generally characterized by chronic inflammation and immune system dysregulation that promote severe, accelerated atherosclerosis beginning
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at an earlier than average age [5-9]. Overall, patients with autoimmune diseases
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demonstrate higher cardiovascular morbidity and mortality, as well as early indications that are typically asymptomatic [5, 6]. In SLE patients, for instance, the risk of
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cardiovascular disease (CVD) is 4-8 times higher than the normal population [10]. Recent
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findings suggest that atherosclerosis is not unavoidable in these populations [9]. Rather, the identification and evaluation of common biomarkers hold tremendous value for the
3.1 Biomarkers of lipid oxidation
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proactive diagnosis and management of CVD in these patients.
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Pro-inflammatory HDL (piHDL) is one such promising biomarker candidate currently under investigation. HDL is a high-density protein complex of
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particles that includes anti-oxidant enzymes and plays a role in the immune system by promoting or repressing inflammation accordingly [11-13]. When acute or chronic inflammation occurs, HDL becomes enriched with free fatty acids, triglycerides, and prooxidants, which yields piHDL that in turn, oxidizes LDL [14]. One’s genetic background and the degree of inflammation seem to determine the degree to which protective HDL or non-protective piHDL are present [12]. Both SLE and rheumatoid arthritis (RA) patients demonstrate significant levels of piHDL, with over 90% of SLE patients with plaque having considerable piHDL levels [12]. The presence of piHDL increases the risk for carotid plaque by over 9-fold, which consequently increases the risk for atherosclerosis, all of which supports piHDL as a strong biomarker candidate for CVD in autoimmune diseases [14-19].
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ACCEPTED MANUSCRIPT 6 A 2010 study illustrated that a mouse model of SLE fed a high fat diet showed increased piHDL and atherosclerosis relative to controls, which showed elevated LDL
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and no atherosclerosis [17]. When injections of leptin hormone were administered to the
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mice, piHDL and atherosclerosis were further increased [17]. High leptin levels and low amounts of physical activity are positively correlated with piHDL and a greater risk for
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CVD in human SLE patients as well, with leptin levels themselves representing a
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possible biomarker [19, 20]. In 2015, a study revealed that HDL complexes themselves are altered in SLE patients, where paraoxanase-3 (PON3) – a powerful anti-oxidant – was
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reduced in those with subclinical atherosclerosis [21]. These findings recommend PON3 as a both a biomarker as well as a potential therapeutic agent [21].
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3.2 Imaging Biomarkers
Atherosclerosis represents the formation, development, and rupture of plaques,
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prompting closer scrutiny into the clinical biomarkers of disease that might be assessed via imaging such as coronary artery calcium (CAC), plaque, rigidity, and intima media thickness (IMT) [6, 7, 16]. Aortic stiffness, as evaluated by pulse wave velocity, has been found to be independently associated with SLE-specific variables, including inflammation, immune dysregulation, and complement activation, particularly in premenopausal patients [22, 23]. The greater the stiffness, the higher the plaque burden and mean arterial pressure in SLE patients, suggesting arterial stiffness may be an early indicator of vascular disease [22, 23]. Electron beam computed tomography illustrates that women with SLE have increased perivascular adipose tissue (PVAT) than healthy controls and that PVAT is significantly correlated with vascular calcification, indicating that female SLE patients
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ACCEPTED MANUSCRIPT 7 may carry adipose differently than healthy controls [24]. Electron beam computed tomography has also uncovered that female patients with SLE and RA were more likely
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(48% versus 35%) to have higher degrees of CAC, at least partially due to the increased
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inflammation and endothelial activation found in those populations [8] and that African American SLE patients demonstrated differences in carotid plaque levels as compared to
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Caucasian SLE patients which were not observed in control populations of each race
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[25].
Carotid ultra sound and contrast enhancement with coronary magnetic resonance
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(CMR) have proven valuable in predicting CVD in SLE patients. In female SLE patients that had not had a previous CV event (MI, angina, transient ischemic attack, coronary
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angioplasty and/or cerebrovascular event), carotid ultra sound found that IMT and plaque were predictive of a future CV event, regardless of associated risk factors or medications
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[26, 27]. CMR has also been useful in identifying vessel injury and at risk individuals within the SLE population [28]. A 2014 prospective cohort study investigated whether traditional risk factors and some of the biomarker candidates mentioned above (piHDL, leptin, IMT, plaque, and piHDL) could be combined to create an overall risk profile using Salford Predictive Modeling software [29]. The study reported that age, total cholesterol, increased LDL, and dyslipidemia predicted carotid plaque in both SLE and controls, yet in SLE, higher BMI, a family history of CVD, a family history of diabetes, longer disease duration, and higher homocysteine levels were additionally significant [29]. Those SLE patients determined “high risk” by the investigators (with three or more positive biomarkers and/or one positive biomarker with a family history of diabetes) had a 28-fold greater
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ACCEPTED MANUSCRIPT 8 chance of the presence of plaque [29]. However, no single biomarker variable had good negative or positive predictive values [29].
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3.3 Biomarkers of abnormal complement activation
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Cell-bound complement activation products (CB-CAPs) have also been identified as potential biomarkers of CVD in patients with SLE. Abnormal levels of activated
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complement deposition product C4d on erythrocytes were first reported in 2004, with
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SLE patients having higher erythrocyte-bound C4d and lower complement receptor 1 levels than patients with other diseases or healthy controls [30, 31]. Subsequent efforts
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demonstrated that platelets bearing C4d (PC4d) was highly specific for a diagnosis of SLE with specificities of 99% and 100% versus other inflammatory diseases and healthy
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controls, respectively. Additional evidence suggested that complement deposition on platelets renders them pro-thrombotic, thus increasing the chances of a venous event [32].
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Observations that SLE patients have significantly higher levels of complement components C1q, C3d, and C4d on their platelets than do controls, suggests an activated classical complement pathway, with 48% of SLE patients but only 4% of controls testing positive for C4d [32]. Platelet-bound complement proteins are present in 18% of SLE patients and may signal those with a worse clinical prognosis due to cerebrovascular complications, as the presence of C4d has been associated with all-cause mortality and stroke in patients with SLE [33]. PC4d may be an important link among the complement system, platelets, thrombosis and autoimmunity [33]. The deposition of C4d on platelets has also been associated with arterial thrombotic events in patients with SLE and antiphospholipid (aPL) syndrome, further suggesting an increased capacity to initiate the classical complement pathway [34]. aPLs
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ACCEPTED MANUSCRIPT 9 can potentially promote complement activation by at least two different pathways in SLE patients [35]. However, in some cases, patients have shown significant C4d and C1q
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platelet deposition but have lacked detectable levels of aPLs [35]. Further investigation of
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complement activation as a source of biomarkers for CVD manifestations of SLE and possibly other autoimmune diseases is clearly warranted.
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4.0 Biomarkers in CV Manifestations of Rheumatoid Arthritis
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4.1 Genetic biomarkers
Autoimmune disorders share an expanding list of risk loci within the genome. The
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human lymphocyte antigen (HLA) haplotype DRB1 within the major histocompatibility complex represents the strongest genetic risk factor for RA and has a number of different
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alleles with varying associated degrees of risk for both RA and CVD [12, 36]. The “shared epitope” (SE) theory states that a conserved amino acid sequence within the
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HLA-DR molecule contributes to the pathogenesis of RA by displaying peptides to arthritogenic T cells [36]. HLA-SE alleles are thought to be predictive of disease outcome, and those patients with two copies of the SE alleles have demonstrated a 2-fold increase in CVD-associated mortality [36]. 4.2 Endothelial dysfunction
A plethora of endothelial dysfunction markers correlate with CVD in RA. Higher levels of adhesion molecules ICAM and VCAM, CRP, IL1, IL6, and TNFα have all been found in RA patients with CVD, but these molecules alone were not fully responsible for the differences between RA patients and controls [37-39]. Increased endothelial dysfunction and enhanced atherosclerosis in the carotid arteries of RA patients, with elevated amounts of CD4+/CD28- T cells in peripheral blood, have also been
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ACCEPTED MANUSCRIPT 10 demonstrated relative to controls [38]. Endothelial progenitor cells (EPCs), normally released during acute vascular injury, are reduced and/or dysfunctional in RA patients
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with atherosclerosis [38].
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A recent study linked the endothelial dysfunction biomarker CRP with two other soluble biomarkers to provide a predictor of CV risk within the general population [40].
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Neurohormone NT-pro brain naturetic protein (NT-proBNP), which is expressed during
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hypoxia, and Troponin I, a regulatory protein complex involved in muscle contraction, combined with CRP significantly enhanced the prediction of CV risk in middle-aged men
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and women, which suggests that this panel could easily be applied to RA patients in the future [40]. Furthermore, these biomarkers have the advantage of being highly stable in
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laboratory samples, making them amenable to repeated testing over prolonged periods of time [40].
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5.0 Other Autoimmune Diseases 5.1 Type I Diabetes (T1D)
CVD represents the foremost cause of mortality and morbidity in T1D patients as the long-term infusion of insulin promotes an environment of chronic inflammation and subsequent endothelial dysfunction [41]. This produces a vicious cycle as proinflammatory cytokines initiated by endothelial dysfunction exacerbate insulin-mediated glucose uptake and vascular inflammation [41]. In the past, the risk of CVD in T1D patients has been underestimated, as T1D patients are younger at disease onset than T2D patients, but recent evidence suggests the CVD risk in this population is considerable [41].
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ACCEPTED MANUSCRIPT 11 One biomarker candidate of CVD in T1D patients includes YKL-40, an excreted inflammatory glycoprotein used to initiate the innate immune system, remodel the
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extracellular matrix, and prompt monocyte to macrophage maturation [42]. Levels of this
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protein are independently correlated to coronary artery disease and may provide an indication of disease presence and progression, as well as an associated mortality risk
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[42]. Other potential markers of CVD in this population include CRP, adhesion
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molecules, monocyte function, nitrotyrosine levels, IL1, and IL6 [43]. 5.2 Sjögren’s Syndrome (SS)
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SS is an autoimmune disease that primarily affects the exocrine system of middleaged women with a pathophysiology that closely mimics SLE, including elevated risk for
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hypertension and dyslipidemia [44]. A marker of subclinical atherosclerosis, pulse wave velocity, was significantly greater in women with SS than controls, even those with no
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history of CVD [44]. SS patients also experience more instances of hypertension, enhanced endothelial dysfunction, increased arterial stiffness, and increased IMT than healthy controls [44]. aPLs are another major component of SS, with the lupus coagulant a key marker of aPL syndrome in SS patients [45]. Many other autoantibodies are linked to SS with potential roles in CVD, including anti-cardiolipins, IgG, and anti-HDL [9]. 5.3 Psoriatic Arthritis (PsA) Recent studies are proving PsA to be a systemic disease akin to SLE and RA, rather than a disease confined to skin and joints [46]. Like SLE and RA, PsA patients have a heightened risk for CVD-associated mortality [46]. There is a well-established TNFα component to PsA that is being addressed with TNFα-inhibiting therapeutics [46, 47]. PsA shares many biomarkers with other autoimmune diseases, such as VEGF, P
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ACCEPTED MANUSCRIPT 12 selectin (a marker of platelet activation), the adipokines resistin and leptin, insulin resistance markers, and markers of endothelial dysfunction [46, 47]. Disease status, age,
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and triglyceride levels have also been correlated with carotid plaque in PsA patients [48],
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and several studies report elevated CRP levels in those with the disease [46, 47, 49]. Consequently, evidence supports categorizing PsA as an independent risk factor for CVD
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[46, 47].
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A 2011 prospective longitudinal observational study of CVD biomarkers associated with PsA demonstrated that PsA patients treated with biologics such as
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etanercept, adalimumab, ustekinumab, and/or fumaric acid esters, cyclosporine, or methotrexate over a period of 24 weeks displayed greatly reduced serum levels of VEGF
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(indicator of hypoxia and inflammation), CRP (a predictor of CVD), and resistin (associated with insulin resistance) [46]. The longer the patients were on therapy, the
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more controlled the disease state and marker levels became [46]. 5.4 Antiphospholipid (aPL) Syndrome aPL syndrome – defined as the correlation between the presence of autoantibodies and an environment of hypercoagulation – aPLs are found in 1-5% of young, healthy patients and only increase as the individual ages [50]. aPLs exist in the absence of clinical disease, and yet 50-70% of SLE patients will eventually test positive for them and their associated risk of venous thrombosis, MI, and recurrent stroke [50]. One of the most well studied autoantibodies is anti-β2 glycoprotein 1 (β2GPI) – a phospholipid-binding plasma protein – key to antibody-mediated thrombotic diseases [51]. Anti-β2GPI and anti-oxLDL/β2GPI antibodies are the most common and consistent antibodies in those with coronary syndromes and are especially associated with coronary
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ACCEPTED MANUSCRIPT 13 plaque and pro-thrombotic aspects [51]. Anti-β2GPI and anti-oxLDL/β2GPI complexes are activated by pro-atherosclerotic inflammation and are greatly increased in those with
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acute coronary syndromes, where they correlate with CV disease severity and risks for
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thrombosis and future CV events [52, 53]. 6.0 Atherosclerosis as an Autoimmune Disease
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The link between CVD and autoimmune diseases is now clear, and it appears that
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the relationship between accelerated atherosclerosis and autoimmune diseases is far more intimate than initially suspected. This begs the question: Is CVD an autoimmune disease?
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The theory of atherosclerosis as an autoimmune disease in its own right was first postulated in 1992 [54]. In the past, atherosclerosis has been principally tied to
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dyslipidemia, which prompted the wide-spread usage of LDL-lowering and HDL-raising therapeutics, such as statins [55]. It has only been within the past decade that research
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relegated lipids to only one portion of the entire atherosclerosis picture [55]. The common themes that CVD shares with autoimmune diseases: inflammation/immune activation, lipid peroxidation, endothelial dysfunction, coagulation, and others are well established, strongly supporting the characterization of atherosclerosis as an autoimmune disorder of the cardiovascular system [6, 51, 52]. One theory of atherosclerotic autoimmunity is, at least in part, based on the premise that all humans develop healthy antibodies against bacterial and parasitic HSP60. When autologous HSP60 and cell adhesion molecules form on the surface of disintegrating cells, a molecular and cellular cascade of events triggers both autoimmunity and cardiovascular disease [54].
7.0 Conclusions and Future Directions
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ACCEPTED MANUSCRIPT 14 CVD manifestations of autoimmune diseases are the leading cause of premature mortality among these conditions. Although this observation was first made among
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patients with SLE, it is also now well documented in rheumatoid arthritis, psoriatic
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arthritis and other rheumatic diseases. As the link between CVD and autoimmune disease becomes broader and tighter, it is essential to discover biomarkers to identify patients
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who are at risk to guide targeted intervention and prevention. Many promising avenues of
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investigation are underway, only some of which have been discussed here (Table I). The complicated nature of these diseases suggests that no single CVD biomarker will be
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sufficient to meet the clinical needs of patients with autoimmune diseases but rather a
8.0 References
Hollan, I., et al., Cardiovascular disease in autoimmune rheumatic diseases.
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1.
TE
D
panel or perhaps an arsenal of biomarkers will ultimately be required.
Autoimmun Rev, 2013. 12(10): p. 1004-15. 2.
Ahearn, J.M., et al., Biomarkers for systemic lupus erythematosus. Transl Res, 2012. 159(4): p. 326-42.
3.
Ahearn, J.M., C.C. Liu, and S. Manzi, Lupus biomarker discovery, validation, approval, and impact on clinical trials. Current Treatment Options in Rheumatology, 2015.
4.
Ahearn, J.M., S. Manzi, and C.C. Liu, The lupus biomarker odyssey: one experience. Methods Mol Biol, 2014. 1134: p. 17-35.
RJ Palmer Freelance Writing LLC
ACCEPTED MANUSCRIPT 15 5.
Manzi, S., et al., Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham
Matsuura, E., et al., Is atherosclerosis an autoimmune disease? BMC Med, 2014.
RI
6.
PT
Study. Am J Epidemiol, 1997. 145(5): p. 408-15.
12: p. 47.
Kao, A.H., J.M. Sabatine, and S. Manzi, Update on vascular disease in systemic
SC
7.
8.
NU
lupus erythematosus. Curr Opin Rheumatol, 2003. 15(5): p. 519-27. Kao, A.H., et al., C-reactive protein and coronary artery calcium in
MA
asymptomatic women with systemic lupus erythematosus or rheumatoid arthritis. Am J Cardiol, 2008. 102(6): p. 755-60.
D
Amaya-Amaya, J., L. Montoya-Sanchez, and A. Rojas-Villarraga, Cardiovascular
TE
9.
involvement in autoimmune diseases. Biomed Res Int, 2014. 2014: p. 367359. Teixeira, P.C., et al., Biomarkers for cardiovascular risk assessment in
AC CE P
10.
autoimmune diseases. Proteomics Clin Appl, 2015. 9(1-2): p. 48-57. 11.
Hahn, B.H., et al., Altered lipoprotein metabolism in chronic inflammatory states: proinflammatory high-density lipoprotein and accelerated atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Res Ther, 2008. 10(4): p. 213.
12.
Hahn, B.H., et al., The pathogenesis of atherosclerosis in autoimmune rheumatic diseases: roles of inflammation and dyslipidemia. J Autoimmun, 2007. 28(2-3): p. 69-75.
13.
Hahn, B.H. and M. McMahon, Atherosclerosis and systemic lupus erythematosus: the role of altered lipids and of autoantibodies. Lupus, 2008. 17(5): p. 368-70.
RJ Palmer Freelance Writing LLC
ACCEPTED MANUSCRIPT 16 14.
McMahon, M., et al., Proinflammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid
McMahon, M., et al., Dysfunctional proinflammatory high-density lipoproteins
RI
15.
PT
arthritis. Arthritis Rheum, 2006. 54(8): p. 2541-9.
confer increased risk of atherosclerosis in women with systemic lupus
McMahon, M. and B.H. Hahn, Atherosclerosis and systemic lupus erythematosus:
NU
16.
SC
erythematosus. Arthritis Rheum, 2009. 60(8): p. 2428-37.
mechanistic basis of the association. Curr Opin Immunol, 2007. 19(6): p. 633-9. Hahn, B.H., et al., Pro-inflammatory high-density lipoproteins and
MA
17.
atherosclerosis are induced in lupus-prone mice by a high-fat diet and leptin.
18.
TE
D
Lupus, 2010. 19(8): p. 913-7.
Skaggs, B.J., et al., Dysfunctional, pro-inflammatory HDL directly upregulates
AC CE P
monocyte PDGFRbeta, chemotaxis and TNFalpha production. Clin Immunol, 2010. 137(1): p. 147-56. 19.
Volkmann, E.R., et al., Low physical activity is associated with proinflammatory high-density lipoprotein and increased subclinical atherosclerosis in women with systemic lupus erythematosus. Arthritis Care Res (Hoboken), 2010. 62(2): p. 25865.
20.
McMahon, M., et al., High plasma leptin levels confer increased risk of atherosclerosis in women with systemic lupus erythematosus, and are associated with inflammatory oxidised lipids. Ann Rheum Dis, 2011. 70(9): p. 1619-24.
RJ Palmer Freelance Writing LLC
ACCEPTED MANUSCRIPT 17 21.
Marsillach, J., et al., Paraoxonase-3 Is Depleted from the High-Density Lipoproteins of Autoimmune Disease Patients with Subclinical Atherosclerosis. J
Selzer, F., et al., Vascular stiffness in women with systemic lupus erythematosus.
RI
22.
PT
Proteome Res, 2015.
Hypertension, 2001. 37(4): p. 1075-82.
Selzer, F., et al., Comparison of risk factors for vascular disease in the carotid
SC
23.
NU
artery and aorta in women with systemic lupus erythematosus. Arthritis Rheum, 2004. 50(1): p. 151-9.
Shields, K.J., et al., Perivascular adipose tissue of the descending thoracic aorta
MA
24.
is associated with systemic lupus erythematosus and vascular calcification in
25.
TE
D
women. Atherosclerosis, 2013. 231(1): p. 129-35. Rhew, E.Y., et al., Differences in subclinical cardiovascular disease between
AC CE P
African American and Caucasian women with systemic lupus erythematosus. Transl Res, 2009. 153(2): p. 51-9. 26.
Kao, A.H., et al., Relation of carotid intima-media thickness and plaque with incident cardiovascular events in women with systemic lupus erythematosus. Am J Cardiol, 2013. 112(7): p. 1025-32.
27.
Thompson, T., et al., Progression of carotid intima-media thickness and plaque in women with systemic lupus erythematosus. Arthritis Rheum, 2008. 58(3): p. 83542.
28.
Varma, N., et al., Coronary vessel wall contrast enhancement imaging as a potential direct marker of coronary involvement: integration of findings from CAD and SLE patients. JACC Cardiovasc Imaging, 2014. 7(8): p. 762-70.
RJ Palmer Freelance Writing LLC
ACCEPTED MANUSCRIPT 18 29.
McMahon, M., et al., A panel of biomarkers is associated with increased risk of the presence and progression of atherosclerosis in women with systemic lupus
Manzi, S., et al., Measurement of erythrocyte C4d and complement receptor 1 in
RI
30.
PT
erythematosus. Arthritis Rheumatol, 2014. 66(1): p. 130-9.
systemic lupus erythematosus. Arthritis Rheum, 2004. 50(11): p. 3596-604. Navratil, J.S., et al., Platelet C4d is highly specific for systemic lupus
SC
31.
32.
NU
erythematosus. Arthritis Rheum, 2006. 54(2): p. 670-4. Lood, C., et al., Increased C1q, C4 and C3 deposition on platelets in patients with
2012. 21(13): p. 1423-32.
D
Kao, A.H., et al., Relation of platelet C4d with all-cause mortality and ischemic
TE
33.
MA
systemic lupus erythematosus--a possible link to venous thrombosis? Lupus,
stroke in patients with systemic lupus erythematosus. Transl Stroke Res, 2014.
34.
AC CE P
5(4): p. 510-8.
Peerschke, E.I., et al., Serum complement activation on heterologous platelets is associated with arterial thrombosis in patients with systemic lupus erythematosus and antiphospholipid antibodies. Lupus, 2009. 18(6): p. 530-8.
35.
Lood, C., et al., Platelet activation and anti-phospholipid antibodies collaborate in the activation of the complement system on platelets in systemic lupus erythematosus. PLoS One, 2014. 9(6): p. e99386.
36.
Rodriguez-Rodriguez, L., et al., Rheumatoid arthritis: genetic variants as biomarkers of cardiovascular disease. Curr Pharm Des, 2015. 21(2): p. 182-201.
RJ Palmer Freelance Writing LLC
ACCEPTED MANUSCRIPT 19 37.
Dessein, P.H., B.I. Joffe, and S. Singh, Biomarkers of endothelial dysfunction, cardiovascular risk factors and atherosclerosis in rheumatoid arthritis. Arthritis
Kaplan, M.J., Cardiovascular complications of rheumatoid arthritis: assessment,
RI
38.
PT
Res Ther, 2005. 7(3): p. R634-43.
prevention, and treatment. Rheum Dis Clin North Am, 2010. 36(2): p. 405-26. Solomon, D.H., et al., Cardiovascular risk factors in women with and without
SC
39.
40.
NU
rheumatoid arthritis. Arthritis Rheum, 2004. 50(11): p. 3444-9. Kozera, L., J. Andrews, and A.W. Morgan, Cardiovascular risk and rheumatoid
MA
arthritis--the next step: differentiating true soluble biomarkers of cardiovascular
41.
TE
50(11): p. 1944-54.
D
risk from surrogate measures of inflammation. Rheumatology (Oxford), 2011.
Libby, P., et al., Report of the National Heart, Lung, and Blood Institute-National
AC CE P
Institute of Diabetes and Digestive and Kidney Diseases Working Group on Cardiovascular Complications of Type 1 Diabetes Mellitus. Circulation, 2005. 111(25): p. 3489-93. 42.
Rathcke, C.N. and H. Vestergaard, YKL-40--an emerging biomarker in cardiovascular disease and diabetes. Cardiovasc Diabetol, 2009. 8: p. 61.
43.
Devaraj, S., et al., Increased monocytic activity and biomarkers of inflammation in patients with type 1 diabetes. Diabetes, 2006. 55(3): p. 774-9.
44.
Sabio, J.M., et al., Prevalence of and factors associated with increased arterial stiffness in patients with primary Sjogren's Syndrome. Arthritis Care & Research, 2015. 67(4): p. 554-562.
RJ Palmer Freelance Writing LLC
ACCEPTED MANUSCRIPT 20 45.
Pasoto, S.G., et al., Lupus anticoagulant: a marker for stroke and venous thrombosis in primary Sjogren's syndrome. Clin Rheumatol, 2012. 31(9): p. 1331-
Boehncke, S., et al., Effective continuous systemic therapy of severe plaque-type
RI
46.
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8.
psoriasis is accompanied by amelioration of biomarkers of cardiovascular risk:
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results of a prospective longitudinal observational study. J Eur Acad Dermatol
47.
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Venereol, 2011. 25(10): p. 1187-93.
Boehncke, W.H. and S. Boehncke, Cardiovascular mortality in psoriasis and
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psoriatic arthritis: epidemiology, pathomechanisms, therapeutic implications, and perspectives. Curr Rheumatol Rep, 2012. 14(4): p. 343-8.
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Eder, L., et al., Subclinical atherosclerosis in psoriatic arthritis: a case-control
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study. The Journal of Rheumatology, 2015. 35(5): p. 877-882. Strober, B., et al., Effects of etanercept on C-reactive protein levels in psoriasis
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49.
and psoriatic arthritis. Br J Dermatol, 2008. 159(2): p. 322-30. 50.
Levine, J.S., D.W. Branch, and J. Rauch, The antiphospholipid syndrome. N Engl J Med, 2002. 346(10): p. 752-63.
51.
Greco, T.P., et al., Newer antiphospholipid antibodies predict adverse outcomes in patients with acute coronary syndrome. Am J Clin Pathol, 2009. 132(4): p. 613-20.
52.
Greco, T.P., et al., Oxidized-LDL/beta(2)-glycoprotein I complexes are associated with disease severity and increased risk for adverse outcomes in patients with acute coronary syndromes. Am J Clin Pathol, 2010. 133(5): p. 737-43.
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Mahler, M., et al., Autoantibodies to domain 1 of beta 2 glycoprotein 1: a promising candidate biomarker for risk management in antiphospholipid
Grundtman, C. and G. Wick, The autoimmune concept of atherosclerosis. Curr
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54.
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syndrome. Autoimmun Rev, 2012. 12(2): p. 313-7.
Opin Lipidol, 2011. 22(5): p. 327-34.
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Zhao, Q., Inflammation, autoimmunity, and atherosclerosis. Discov Med, 2009.
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8(40): p. 7-12.
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55.
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Table I Cardiovascular Disease Biomarkers Across Autoimmune Diseases
piHDL
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Coronary plaque
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Vessel rigidity
HLA haplotype DRB1
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RA
Adhesion molecules ICAM and VCAM CRP
TNFα IL1/6 CD4+/CD28- T cells
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Atherosclerosis: Presence of pro-inflammatory HDL increases risk of carotid plaque by 9 fold which enhances risk of atherosclerosis; 90% of SLE patients with plaque show significant levels of piHDL Atherosclerosis and Cardiac Events*: Patients with SLE and RA more likely to have high levels of CAC, a component of atherosclerotic plaques; CAC level is predictive of future cardiac event Atherosclerosis and Cardiac Events: Formation and rupture of plaque defines atherosclerosis; greater plaque burden yields increased risk for atherosclerosis; plaque burden is predictive of future cardiac event Atherosclerosis: the greater the stiffness, the higher the plaque burden and mean arterial pressure in SLE patients; also independently associated with inflammation, complement activation, and immune dysregulation components of atherosclerosis Cardiac Events: predictive of future cardiac event Thrombosis: positively associated with arterial thrombotic events; correlated with all-cause mortality and stroke in SLE patients; sign of abnormal complement activation; might indicate those with worse prognosis; Cardiovascular Disease-Associated Mortality: RA patients with two copies of this genetic marker demonstrate a 2-fold increase in cardiovascular disease-associated mortality Endothelial Dysfunction CVD: higher levels found in RA patients with CVD
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CAC
IMT C4d, etc.
Association
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SLE
Biomarker
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Disease
YKL-40
Adhesion molecules CRP Nitrotyrosine levels
Endothelial Dysfunction CVD: higher levels found in RA patients with CVD; predictor of CV risk in general population Endothelial Dysfunction CVD: higher levels found in RA patients with CVD Endothelial Dysfunction CVD: higher levels found in RA patients with CVD Endothelial Dysfunction CVD: higher levels found in RA patients with CVD; elevated levels found in peripheral blood linked to enhanced atherosclerosis Coronary Artery Disease: independently associated with coronary artery disease in T1D patients; may indicate disease presence, progression, and mortality risk CVD and Thrombosis: positively correlated with CVD in T1D patients CVD: positively correlated with CVD in T1D patients CVD: positively correlated with CVD in T1D patients
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VEGF Adipokines resistin and lepin
aPL syndrome
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CRP
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PsA
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aPLs such as anticardiolipin and IgG TNFα
anti-β2GPI
anti-oxLDL/β2GPI
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SS
CVD: positively correlated with CVD in T1D patients Atherosclerosis: indicator of subclinical atherosclerosis; correlated with hypertension, increased arterial stiffness, and increased IMT relative to controls Atherosclerosis, Arterial Thrombosis, CVD: associated with aPL syndrome which shows increased risks for thrombosis, ischemic stroke, and plaque CVD: when TNFα-inhibiting therapeutics are administered continuously, disease severity and traditional CV risk factors (CRP, leptin, VEGF) in PsA patients decline Systemic Inflammation and Disease Severity: positively correlated with both in PsA patients Thrombosis and Insulin Resistance: upregulate adhesion molecules which promotes thrombosis and are positively correlated with insulin resistance Atherosclerosis, Systemic Inflammation, CVD: associated with plaque levels, inflammation levels, and risk of CVD Thrombosis, MI, and Stroke: positively associated with hypercoagulation, plaque, CV disease severity, and risks for future cardiovascular events Thrombosis, MI, and Stroke: positively associated with hypercoagulation, plaque, CV disease severity, and risks for future cardiovascular events
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IL1/6 Pulse wave velocity
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Abbreviations: SLE – systemic lupus erythematosus, piHDL – pro-inflammatory high density lipoproteins, CAC – coronary artery calcium, IMT – intima media thickness, RA – rheumatoid arthritis, I/VCAM – intercellular/vascular cell adhesion molecule, CRP – C reactive protein, IL1/6 – interleukins, TNFα – tumor necrosis factor α, T1D – Type I diabetes, SS - Sjögren’s Syndrome, aPLs – antiphospholipids, PsA – psoriatic arthritis, VEGF – vascular endothelial growth factor, anti-β2GPI – anti-β2 glycoprotein 1
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ACCEPTED MANUSCRIPT 24 HIGHLIGHTS
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Cardiovascular disease (CVD) is a leading cause of premature mortality in patients with autoimmune diseases
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Biomarkers are essential to identify, monitor and stratify those at risk for CVD complications of autoimmune diseases
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Current areas of focus in CVD biomarker investigation include imaging modalities as well as biomarkers to reflect complement activation, endothelial dysfunction, and other aspects of inflammation and immune dysregulation
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S1521-6616(15)00220-X doi: 10.1016/j.clim.2015.05.024 YCLIM 7515
To appear in:
Clinical Immunology
Received date: Accepted date:
26 April 2015 13 May 2015
Please cite this article as: Joseph Ahearn, Kelly J. Shields, Chau-Ching Liu, Susan Manzi, Cardiovascular disease biomarkers across autoimmune diseases, Clinical Immunology (2015), doi: 10.1016/j.clim.2015.05.024
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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TITLE: Cardiovascular disease biomarkers across autoimmune diseases
Authors, Affiliations, and Email addresses:
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Joseph Ahearn, MD, Kelly J. Shields, PhD, Chau-Ching Liu, MD, PhD, Susan Manzi,
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MD, MPH Lupus Center of Excellence
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Autoimmunity Institute
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Corresponding author:
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Allegheny Health Network
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Department of Medicine
Joseph M. Ahearn, MD Allegheny Health Network Pittsburgh, PA 15212 [email protected]
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ABSTRACT:
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Cardiovascular disease is increasingly recognized a major cause of premature mortality
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among those with autoimmune disorders. There is an urgent need to identify those patients with autoimmune disease who are at risk for CVD so as to optimize therapeutic
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intervention and ultimately prevention. Accurate identification, monitoring and
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stratification of such patients will depend upon a panel of biomarkers of cardiovascular disease. This review will discuss some of the most recent biomarkers of cardiovascular
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diseases in autoimmune disease, including lipid oxidation, imaging biomarkers to characterize coronary calcium, plaque, and intima media thickness, biomarkers of
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inflammation and activated complement, genetic markers, endothelial biomarkers, and antiphospholipid antibodies. Clinical implementation of these biomarkers will not only
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enhance patient care but also likely accelerate the pharmaceutical pipeline for targeted intervention to reduce or eliminate cardiovascular disease in the setting of autoimmunity.
KEYWORDS: autoimmune, lupus, rheumatoid, atherosclerosis, biomarkers, cardiovascular
ABBREVIATIONS1
ACKNOWLEDGEMENTS
1 Abbreviations: CB-CAPs - cell-bound complement activation products, EPCs - endothelial progenitor cells, IRF –
interferon regulatory factor, LN – lupus nephritis, NT-proBNP – neurohormone NT-pro brain naturetic protein, piHDL – pro-inflammatory high density lipoprotein, PON3 - paraoxanase-3, PVAT – perivascular adipose tissue, SE – shared epitope
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ACCEPTED MANUSCRIPT 3 We would like to acknowledge Rebecca J. Palmer, PhD for her assistance in the
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preparation of this manuscript.
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1.0 Cardiovascular Diseases in Autoimmunity
Myriad abnormalities of the cardiovascular system have been thoroughly
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described throughout the broad spectrum of autoimmune diseases. Among these, the
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single most common cause of premature mortality in rheumatic conditions is cardiovascular disease in the form of accelerated atherosclerosis [1]. This phenomenon
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was first described in the mid 1990’s in studies of patients with systemic lupus erythematosus (SLE). More recently, similar observations have been made in patients
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with rheumatoid arthritis, psoriatic arthritis, Sjögren’s Syndrome and other rheumatic and autoimmune conditions. Many traditional and non-traditional risk factors are thought to
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contribute to this premature development of cardiovascular disease (CVD) in the context of autoimmunity, including factors such as inflammation, immune system dysfunction, lipoproteins levels, hypertension, insulin resistance, obesity, complement deposition on platelets, irregularities in endothelial progenitor cells, vitamin D deficiencies, and more [1]. Recent evidence suggests that a combination of infection and autoimmunity may promote vascular inflammation and dysfunction in endothelial cells, which accelerates the pathogenesis of CVD in these individuals. There is an urgent need to identify risk factors for CVD in patients with autoimmune diseases. This will facilitate targeted intervention, prevention, and ultimately decrease or eliminate the high risk of morbidity and mortality due to CVD in these patient populations. This review will discuss some of
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ACCEPTED MANUSCRIPT 4 the most promising areas of investigation in efforts to identify and validate biomarkers to aid in these efforts.
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2.0 The Nature and Importance of Biomarkers
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A biomarker is defined as a qualitatively or quantitatively measureable molecule, gene, biochemical, biological event, or imaging event that, when altered, may be
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correlated with a disease pathogenesis/manifestation [2, 3]. As such, biomarkers are
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objective signs, as opposed to subjective symptoms, of illness [3]. Biomarkers are of supreme importance in autoimmune disease because of the inherent complexity of
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diagnosis, monitoring, and predicting outcomes of these multifaceted diseases, which rely upon the accurate interpretation of numerous clinical and laboratory measurements of
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multiorgan system pathology [2]. In addition to their importance in patient care, biomarkers are also critical in the drug discovery and approval process. Currently, the
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pharmaceutical pipeline is slowed by clinical endpoints that may be subjective, infrequent, invasive, otherwise unfeasible, and therefore unreliable, assessments of drug candidates [3]. The establishment of standardized biomarkers promises to improve the evaluations of drug candidates as well as better identify patients most likely to respond to them [3, 4]. As the number of identified autoimmune diseases, the number of affected patients, and the annual costs of treating these illnesses continue to escalate, the need for reliable biomarkers of autoimmune disease increases. The search for biomarkers of autoimmune diseases may be no more pressing than in the area of CVD because of the increasingly recognized influence of accelerated atherosclerosis in morbidity and mortality among patients with SLE, RA and beyond. 3.0 Biomarkers in CVD Manifestations of Systemic Lupus Erythematosus
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ACCEPTED MANUSCRIPT 5 Autoimmune diseases are generally characterized by chronic inflammation and immune system dysregulation that promote severe, accelerated atherosclerosis beginning
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at an earlier than average age [5-9]. Overall, patients with autoimmune diseases
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demonstrate higher cardiovascular morbidity and mortality, as well as early indications that are typically asymptomatic [5, 6]. In SLE patients, for instance, the risk of
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cardiovascular disease (CVD) is 4-8 times higher than the normal population [10]. Recent
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findings suggest that atherosclerosis is not unavoidable in these populations [9]. Rather, the identification and evaluation of common biomarkers hold tremendous value for the
3.1 Biomarkers of lipid oxidation
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proactive diagnosis and management of CVD in these patients.
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Pro-inflammatory HDL (piHDL) is one such promising biomarker candidate currently under investigation. HDL is a high-density protein complex of
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particles that includes anti-oxidant enzymes and plays a role in the immune system by promoting or repressing inflammation accordingly [11-13]. When acute or chronic inflammation occurs, HDL becomes enriched with free fatty acids, triglycerides, and prooxidants, which yields piHDL that in turn, oxidizes LDL [14]. One’s genetic background and the degree of inflammation seem to determine the degree to which protective HDL or non-protective piHDL are present [12]. Both SLE and rheumatoid arthritis (RA) patients demonstrate significant levels of piHDL, with over 90% of SLE patients with plaque having considerable piHDL levels [12]. The presence of piHDL increases the risk for carotid plaque by over 9-fold, which consequently increases the risk for atherosclerosis, all of which supports piHDL as a strong biomarker candidate for CVD in autoimmune diseases [14-19].
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ACCEPTED MANUSCRIPT 6 A 2010 study illustrated that a mouse model of SLE fed a high fat diet showed increased piHDL and atherosclerosis relative to controls, which showed elevated LDL
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and no atherosclerosis [17]. When injections of leptin hormone were administered to the
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mice, piHDL and atherosclerosis were further increased [17]. High leptin levels and low amounts of physical activity are positively correlated with piHDL and a greater risk for
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CVD in human SLE patients as well, with leptin levels themselves representing a
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possible biomarker [19, 20]. In 2015, a study revealed that HDL complexes themselves are altered in SLE patients, where paraoxanase-3 (PON3) – a powerful anti-oxidant – was
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reduced in those with subclinical atherosclerosis [21]. These findings recommend PON3 as a both a biomarker as well as a potential therapeutic agent [21].
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3.2 Imaging Biomarkers
Atherosclerosis represents the formation, development, and rupture of plaques,
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prompting closer scrutiny into the clinical biomarkers of disease that might be assessed via imaging such as coronary artery calcium (CAC), plaque, rigidity, and intima media thickness (IMT) [6, 7, 16]. Aortic stiffness, as evaluated by pulse wave velocity, has been found to be independently associated with SLE-specific variables, including inflammation, immune dysregulation, and complement activation, particularly in premenopausal patients [22, 23]. The greater the stiffness, the higher the plaque burden and mean arterial pressure in SLE patients, suggesting arterial stiffness may be an early indicator of vascular disease [22, 23]. Electron beam computed tomography illustrates that women with SLE have increased perivascular adipose tissue (PVAT) than healthy controls and that PVAT is significantly correlated with vascular calcification, indicating that female SLE patients
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ACCEPTED MANUSCRIPT 7 may carry adipose differently than healthy controls [24]. Electron beam computed tomography has also uncovered that female patients with SLE and RA were more likely
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(48% versus 35%) to have higher degrees of CAC, at least partially due to the increased
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inflammation and endothelial activation found in those populations [8] and that African American SLE patients demonstrated differences in carotid plaque levels as compared to
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Caucasian SLE patients which were not observed in control populations of each race
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[25].
Carotid ultra sound and contrast enhancement with coronary magnetic resonance
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(CMR) have proven valuable in predicting CVD in SLE patients. In female SLE patients that had not had a previous CV event (MI, angina, transient ischemic attack, coronary
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angioplasty and/or cerebrovascular event), carotid ultra sound found that IMT and plaque were predictive of a future CV event, regardless of associated risk factors or medications
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[26, 27]. CMR has also been useful in identifying vessel injury and at risk individuals within the SLE population [28]. A 2014 prospective cohort study investigated whether traditional risk factors and some of the biomarker candidates mentioned above (piHDL, leptin, IMT, plaque, and piHDL) could be combined to create an overall risk profile using Salford Predictive Modeling software [29]. The study reported that age, total cholesterol, increased LDL, and dyslipidemia predicted carotid plaque in both SLE and controls, yet in SLE, higher BMI, a family history of CVD, a family history of diabetes, longer disease duration, and higher homocysteine levels were additionally significant [29]. Those SLE patients determined “high risk” by the investigators (with three or more positive biomarkers and/or one positive biomarker with a family history of diabetes) had a 28-fold greater
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ACCEPTED MANUSCRIPT 8 chance of the presence of plaque [29]. However, no single biomarker variable had good negative or positive predictive values [29].
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3.3 Biomarkers of abnormal complement activation
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Cell-bound complement activation products (CB-CAPs) have also been identified as potential biomarkers of CVD in patients with SLE. Abnormal levels of activated
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complement deposition product C4d on erythrocytes were first reported in 2004, with
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SLE patients having higher erythrocyte-bound C4d and lower complement receptor 1 levels than patients with other diseases or healthy controls [30, 31]. Subsequent efforts
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demonstrated that platelets bearing C4d (PC4d) was highly specific for a diagnosis of SLE with specificities of 99% and 100% versus other inflammatory diseases and healthy
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controls, respectively. Additional evidence suggested that complement deposition on platelets renders them pro-thrombotic, thus increasing the chances of a venous event [32].
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Observations that SLE patients have significantly higher levels of complement components C1q, C3d, and C4d on their platelets than do controls, suggests an activated classical complement pathway, with 48% of SLE patients but only 4% of controls testing positive for C4d [32]. Platelet-bound complement proteins are present in 18% of SLE patients and may signal those with a worse clinical prognosis due to cerebrovascular complications, as the presence of C4d has been associated with all-cause mortality and stroke in patients with SLE [33]. PC4d may be an important link among the complement system, platelets, thrombosis and autoimmunity [33]. The deposition of C4d on platelets has also been associated with arterial thrombotic events in patients with SLE and antiphospholipid (aPL) syndrome, further suggesting an increased capacity to initiate the classical complement pathway [34]. aPLs
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ACCEPTED MANUSCRIPT 9 can potentially promote complement activation by at least two different pathways in SLE patients [35]. However, in some cases, patients have shown significant C4d and C1q
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platelet deposition but have lacked detectable levels of aPLs [35]. Further investigation of
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complement activation as a source of biomarkers for CVD manifestations of SLE and possibly other autoimmune diseases is clearly warranted.
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4.0 Biomarkers in CV Manifestations of Rheumatoid Arthritis
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4.1 Genetic biomarkers
Autoimmune disorders share an expanding list of risk loci within the genome. The
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human lymphocyte antigen (HLA) haplotype DRB1 within the major histocompatibility complex represents the strongest genetic risk factor for RA and has a number of different
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alleles with varying associated degrees of risk for both RA and CVD [12, 36]. The “shared epitope” (SE) theory states that a conserved amino acid sequence within the
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HLA-DR molecule contributes to the pathogenesis of RA by displaying peptides to arthritogenic T cells [36]. HLA-SE alleles are thought to be predictive of disease outcome, and those patients with two copies of the SE alleles have demonstrated a 2-fold increase in CVD-associated mortality [36]. 4.2 Endothelial dysfunction
A plethora of endothelial dysfunction markers correlate with CVD in RA. Higher levels of adhesion molecules ICAM and VCAM, CRP, IL1, IL6, and TNFα have all been found in RA patients with CVD, but these molecules alone were not fully responsible for the differences between RA patients and controls [37-39]. Increased endothelial dysfunction and enhanced atherosclerosis in the carotid arteries of RA patients, with elevated amounts of CD4+/CD28- T cells in peripheral blood, have also been
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ACCEPTED MANUSCRIPT 10 demonstrated relative to controls [38]. Endothelial progenitor cells (EPCs), normally released during acute vascular injury, are reduced and/or dysfunctional in RA patients
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with atherosclerosis [38].
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A recent study linked the endothelial dysfunction biomarker CRP with two other soluble biomarkers to provide a predictor of CV risk within the general population [40].
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Neurohormone NT-pro brain naturetic protein (NT-proBNP), which is expressed during
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hypoxia, and Troponin I, a regulatory protein complex involved in muscle contraction, combined with CRP significantly enhanced the prediction of CV risk in middle-aged men
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and women, which suggests that this panel could easily be applied to RA patients in the future [40]. Furthermore, these biomarkers have the advantage of being highly stable in
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laboratory samples, making them amenable to repeated testing over prolonged periods of time [40].
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5.0 Other Autoimmune Diseases 5.1 Type I Diabetes (T1D)
CVD represents the foremost cause of mortality and morbidity in T1D patients as the long-term infusion of insulin promotes an environment of chronic inflammation and subsequent endothelial dysfunction [41]. This produces a vicious cycle as proinflammatory cytokines initiated by endothelial dysfunction exacerbate insulin-mediated glucose uptake and vascular inflammation [41]. In the past, the risk of CVD in T1D patients has been underestimated, as T1D patients are younger at disease onset than T2D patients, but recent evidence suggests the CVD risk in this population is considerable [41].
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ACCEPTED MANUSCRIPT 11 One biomarker candidate of CVD in T1D patients includes YKL-40, an excreted inflammatory glycoprotein used to initiate the innate immune system, remodel the
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extracellular matrix, and prompt monocyte to macrophage maturation [42]. Levels of this
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protein are independently correlated to coronary artery disease and may provide an indication of disease presence and progression, as well as an associated mortality risk
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[42]. Other potential markers of CVD in this population include CRP, adhesion
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molecules, monocyte function, nitrotyrosine levels, IL1, and IL6 [43]. 5.2 Sjögren’s Syndrome (SS)
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SS is an autoimmune disease that primarily affects the exocrine system of middleaged women with a pathophysiology that closely mimics SLE, including elevated risk for
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hypertension and dyslipidemia [44]. A marker of subclinical atherosclerosis, pulse wave velocity, was significantly greater in women with SS than controls, even those with no
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history of CVD [44]. SS patients also experience more instances of hypertension, enhanced endothelial dysfunction, increased arterial stiffness, and increased IMT than healthy controls [44]. aPLs are another major component of SS, with the lupus coagulant a key marker of aPL syndrome in SS patients [45]. Many other autoantibodies are linked to SS with potential roles in CVD, including anti-cardiolipins, IgG, and anti-HDL [9]. 5.3 Psoriatic Arthritis (PsA) Recent studies are proving PsA to be a systemic disease akin to SLE and RA, rather than a disease confined to skin and joints [46]. Like SLE and RA, PsA patients have a heightened risk for CVD-associated mortality [46]. There is a well-established TNFα component to PsA that is being addressed with TNFα-inhibiting therapeutics [46, 47]. PsA shares many biomarkers with other autoimmune diseases, such as VEGF, P
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ACCEPTED MANUSCRIPT 12 selectin (a marker of platelet activation), the adipokines resistin and leptin, insulin resistance markers, and markers of endothelial dysfunction [46, 47]. Disease status, age,
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and triglyceride levels have also been correlated with carotid plaque in PsA patients [48],
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and several studies report elevated CRP levels in those with the disease [46, 47, 49]. Consequently, evidence supports categorizing PsA as an independent risk factor for CVD
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[46, 47].
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A 2011 prospective longitudinal observational study of CVD biomarkers associated with PsA demonstrated that PsA patients treated with biologics such as
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etanercept, adalimumab, ustekinumab, and/or fumaric acid esters, cyclosporine, or methotrexate over a period of 24 weeks displayed greatly reduced serum levels of VEGF
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(indicator of hypoxia and inflammation), CRP (a predictor of CVD), and resistin (associated with insulin resistance) [46]. The longer the patients were on therapy, the
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more controlled the disease state and marker levels became [46]. 5.4 Antiphospholipid (aPL) Syndrome aPL syndrome – defined as the correlation between the presence of autoantibodies and an environment of hypercoagulation – aPLs are found in 1-5% of young, healthy patients and only increase as the individual ages [50]. aPLs exist in the absence of clinical disease, and yet 50-70% of SLE patients will eventually test positive for them and their associated risk of venous thrombosis, MI, and recurrent stroke [50]. One of the most well studied autoantibodies is anti-β2 glycoprotein 1 (β2GPI) – a phospholipid-binding plasma protein – key to antibody-mediated thrombotic diseases [51]. Anti-β2GPI and anti-oxLDL/β2GPI antibodies are the most common and consistent antibodies in those with coronary syndromes and are especially associated with coronary
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ACCEPTED MANUSCRIPT 13 plaque and pro-thrombotic aspects [51]. Anti-β2GPI and anti-oxLDL/β2GPI complexes are activated by pro-atherosclerotic inflammation and are greatly increased in those with
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acute coronary syndromes, where they correlate with CV disease severity and risks for
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thrombosis and future CV events [52, 53]. 6.0 Atherosclerosis as an Autoimmune Disease
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The link between CVD and autoimmune diseases is now clear, and it appears that
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the relationship between accelerated atherosclerosis and autoimmune diseases is far more intimate than initially suspected. This begs the question: Is CVD an autoimmune disease?
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The theory of atherosclerosis as an autoimmune disease in its own right was first postulated in 1992 [54]. In the past, atherosclerosis has been principally tied to
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dyslipidemia, which prompted the wide-spread usage of LDL-lowering and HDL-raising therapeutics, such as statins [55]. It has only been within the past decade that research
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relegated lipids to only one portion of the entire atherosclerosis picture [55]. The common themes that CVD shares with autoimmune diseases: inflammation/immune activation, lipid peroxidation, endothelial dysfunction, coagulation, and others are well established, strongly supporting the characterization of atherosclerosis as an autoimmune disorder of the cardiovascular system [6, 51, 52]. One theory of atherosclerotic autoimmunity is, at least in part, based on the premise that all humans develop healthy antibodies against bacterial and parasitic HSP60. When autologous HSP60 and cell adhesion molecules form on the surface of disintegrating cells, a molecular and cellular cascade of events triggers both autoimmunity and cardiovascular disease [54].
7.0 Conclusions and Future Directions
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ACCEPTED MANUSCRIPT 14 CVD manifestations of autoimmune diseases are the leading cause of premature mortality among these conditions. Although this observation was first made among
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patients with SLE, it is also now well documented in rheumatoid arthritis, psoriatic
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arthritis and other rheumatic diseases. As the link between CVD and autoimmune disease becomes broader and tighter, it is essential to discover biomarkers to identify patients
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who are at risk to guide targeted intervention and prevention. Many promising avenues of
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investigation are underway, only some of which have been discussed here (Table I). The complicated nature of these diseases suggests that no single CVD biomarker will be
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sufficient to meet the clinical needs of patients with autoimmune diseases but rather a
8.0 References
Hollan, I., et al., Cardiovascular disease in autoimmune rheumatic diseases.
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1.
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D
panel or perhaps an arsenal of biomarkers will ultimately be required.
Autoimmun Rev, 2013. 12(10): p. 1004-15. 2.
Ahearn, J.M., et al., Biomarkers for systemic lupus erythematosus. Transl Res, 2012. 159(4): p. 326-42.
3.
Ahearn, J.M., C.C. Liu, and S. Manzi, Lupus biomarker discovery, validation, approval, and impact on clinical trials. Current Treatment Options in Rheumatology, 2015.
4.
Ahearn, J.M., S. Manzi, and C.C. Liu, The lupus biomarker odyssey: one experience. Methods Mol Biol, 2014. 1134: p. 17-35.
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ACCEPTED MANUSCRIPT 15 5.
Manzi, S., et al., Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham
Matsuura, E., et al., Is atherosclerosis an autoimmune disease? BMC Med, 2014.
RI
6.
PT
Study. Am J Epidemiol, 1997. 145(5): p. 408-15.
12: p. 47.
Kao, A.H., J.M. Sabatine, and S. Manzi, Update on vascular disease in systemic
SC
7.
8.
NU
lupus erythematosus. Curr Opin Rheumatol, 2003. 15(5): p. 519-27. Kao, A.H., et al., C-reactive protein and coronary artery calcium in
MA
asymptomatic women with systemic lupus erythematosus or rheumatoid arthritis. Am J Cardiol, 2008. 102(6): p. 755-60.
D
Amaya-Amaya, J., L. Montoya-Sanchez, and A. Rojas-Villarraga, Cardiovascular
TE
9.
involvement in autoimmune diseases. Biomed Res Int, 2014. 2014: p. 367359. Teixeira, P.C., et al., Biomarkers for cardiovascular risk assessment in
AC CE P
10.
autoimmune diseases. Proteomics Clin Appl, 2015. 9(1-2): p. 48-57. 11.
Hahn, B.H., et al., Altered lipoprotein metabolism in chronic inflammatory states: proinflammatory high-density lipoprotein and accelerated atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Res Ther, 2008. 10(4): p. 213.
12.
Hahn, B.H., et al., The pathogenesis of atherosclerosis in autoimmune rheumatic diseases: roles of inflammation and dyslipidemia. J Autoimmun, 2007. 28(2-3): p. 69-75.
13.
Hahn, B.H. and M. McMahon, Atherosclerosis and systemic lupus erythematosus: the role of altered lipids and of autoantibodies. Lupus, 2008. 17(5): p. 368-70.
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ACCEPTED MANUSCRIPT 16 14.
McMahon, M., et al., Proinflammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid
McMahon, M., et al., Dysfunctional proinflammatory high-density lipoproteins
RI
15.
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arthritis. Arthritis Rheum, 2006. 54(8): p. 2541-9.
confer increased risk of atherosclerosis in women with systemic lupus
McMahon, M. and B.H. Hahn, Atherosclerosis and systemic lupus erythematosus:
NU
16.
SC
erythematosus. Arthritis Rheum, 2009. 60(8): p. 2428-37.
mechanistic basis of the association. Curr Opin Immunol, 2007. 19(6): p. 633-9. Hahn, B.H., et al., Pro-inflammatory high-density lipoproteins and
MA
17.
atherosclerosis are induced in lupus-prone mice by a high-fat diet and leptin.
18.
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Lupus, 2010. 19(8): p. 913-7.
Skaggs, B.J., et al., Dysfunctional, pro-inflammatory HDL directly upregulates
AC CE P
monocyte PDGFRbeta, chemotaxis and TNFalpha production. Clin Immunol, 2010. 137(1): p. 147-56. 19.
Volkmann, E.R., et al., Low physical activity is associated with proinflammatory high-density lipoprotein and increased subclinical atherosclerosis in women with systemic lupus erythematosus. Arthritis Care Res (Hoboken), 2010. 62(2): p. 25865.
20.
McMahon, M., et al., High plasma leptin levels confer increased risk of atherosclerosis in women with systemic lupus erythematosus, and are associated with inflammatory oxidised lipids. Ann Rheum Dis, 2011. 70(9): p. 1619-24.
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ACCEPTED MANUSCRIPT 17 21.
Marsillach, J., et al., Paraoxonase-3 Is Depleted from the High-Density Lipoproteins of Autoimmune Disease Patients with Subclinical Atherosclerosis. J
Selzer, F., et al., Vascular stiffness in women with systemic lupus erythematosus.
RI
22.
PT
Proteome Res, 2015.
Hypertension, 2001. 37(4): p. 1075-82.
Selzer, F., et al., Comparison of risk factors for vascular disease in the carotid
SC
23.
NU
artery and aorta in women with systemic lupus erythematosus. Arthritis Rheum, 2004. 50(1): p. 151-9.
Shields, K.J., et al., Perivascular adipose tissue of the descending thoracic aorta
MA
24.
is associated with systemic lupus erythematosus and vascular calcification in
25.
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D
women. Atherosclerosis, 2013. 231(1): p. 129-35. Rhew, E.Y., et al., Differences in subclinical cardiovascular disease between
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African American and Caucasian women with systemic lupus erythematosus. Transl Res, 2009. 153(2): p. 51-9. 26.
Kao, A.H., et al., Relation of carotid intima-media thickness and plaque with incident cardiovascular events in women with systemic lupus erythematosus. Am J Cardiol, 2013. 112(7): p. 1025-32.
27.
Thompson, T., et al., Progression of carotid intima-media thickness and plaque in women with systemic lupus erythematosus. Arthritis Rheum, 2008. 58(3): p. 83542.
28.
Varma, N., et al., Coronary vessel wall contrast enhancement imaging as a potential direct marker of coronary involvement: integration of findings from CAD and SLE patients. JACC Cardiovasc Imaging, 2014. 7(8): p. 762-70.
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McMahon, M., et al., A panel of biomarkers is associated with increased risk of the presence and progression of atherosclerosis in women with systemic lupus
Manzi, S., et al., Measurement of erythrocyte C4d and complement receptor 1 in
RI
30.
PT
erythematosus. Arthritis Rheumatol, 2014. 66(1): p. 130-9.
systemic lupus erythematosus. Arthritis Rheum, 2004. 50(11): p. 3596-604. Navratil, J.S., et al., Platelet C4d is highly specific for systemic lupus
SC
31.
32.
NU
erythematosus. Arthritis Rheum, 2006. 54(2): p. 670-4. Lood, C., et al., Increased C1q, C4 and C3 deposition on platelets in patients with
2012. 21(13): p. 1423-32.
D
Kao, A.H., et al., Relation of platelet C4d with all-cause mortality and ischemic
TE
33.
MA
systemic lupus erythematosus--a possible link to venous thrombosis? Lupus,
stroke in patients with systemic lupus erythematosus. Transl Stroke Res, 2014.
34.
AC CE P
5(4): p. 510-8.
Peerschke, E.I., et al., Serum complement activation on heterologous platelets is associated with arterial thrombosis in patients with systemic lupus erythematosus and antiphospholipid antibodies. Lupus, 2009. 18(6): p. 530-8.
35.
Lood, C., et al., Platelet activation and anti-phospholipid antibodies collaborate in the activation of the complement system on platelets in systemic lupus erythematosus. PLoS One, 2014. 9(6): p. e99386.
36.
Rodriguez-Rodriguez, L., et al., Rheumatoid arthritis: genetic variants as biomarkers of cardiovascular disease. Curr Pharm Des, 2015. 21(2): p. 182-201.
RJ Palmer Freelance Writing LLC
ACCEPTED MANUSCRIPT 19 37.
Dessein, P.H., B.I. Joffe, and S. Singh, Biomarkers of endothelial dysfunction, cardiovascular risk factors and atherosclerosis in rheumatoid arthritis. Arthritis
Kaplan, M.J., Cardiovascular complications of rheumatoid arthritis: assessment,
RI
38.
PT
Res Ther, 2005. 7(3): p. R634-43.
prevention, and treatment. Rheum Dis Clin North Am, 2010. 36(2): p. 405-26. Solomon, D.H., et al., Cardiovascular risk factors in women with and without
SC
39.
40.
NU
rheumatoid arthritis. Arthritis Rheum, 2004. 50(11): p. 3444-9. Kozera, L., J. Andrews, and A.W. Morgan, Cardiovascular risk and rheumatoid
MA
arthritis--the next step: differentiating true soluble biomarkers of cardiovascular
41.
TE
50(11): p. 1944-54.
D
risk from surrogate measures of inflammation. Rheumatology (Oxford), 2011.
Libby, P., et al., Report of the National Heart, Lung, and Blood Institute-National
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Institute of Diabetes and Digestive and Kidney Diseases Working Group on Cardiovascular Complications of Type 1 Diabetes Mellitus. Circulation, 2005. 111(25): p. 3489-93. 42.
Rathcke, C.N. and H. Vestergaard, YKL-40--an emerging biomarker in cardiovascular disease and diabetes. Cardiovasc Diabetol, 2009. 8: p. 61.
43.
Devaraj, S., et al., Increased monocytic activity and biomarkers of inflammation in patients with type 1 diabetes. Diabetes, 2006. 55(3): p. 774-9.
44.
Sabio, J.M., et al., Prevalence of and factors associated with increased arterial stiffness in patients with primary Sjogren's Syndrome. Arthritis Care & Research, 2015. 67(4): p. 554-562.
RJ Palmer Freelance Writing LLC
ACCEPTED MANUSCRIPT 20 45.
Pasoto, S.G., et al., Lupus anticoagulant: a marker for stroke and venous thrombosis in primary Sjogren's syndrome. Clin Rheumatol, 2012. 31(9): p. 1331-
Boehncke, S., et al., Effective continuous systemic therapy of severe plaque-type
RI
46.
PT
8.
psoriasis is accompanied by amelioration of biomarkers of cardiovascular risk:
SC
results of a prospective longitudinal observational study. J Eur Acad Dermatol
47.
NU
Venereol, 2011. 25(10): p. 1187-93.
Boehncke, W.H. and S. Boehncke, Cardiovascular mortality in psoriasis and
MA
psoriatic arthritis: epidemiology, pathomechanisms, therapeutic implications, and perspectives. Curr Rheumatol Rep, 2012. 14(4): p. 343-8.
D
Eder, L., et al., Subclinical atherosclerosis in psoriatic arthritis: a case-control
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48.
study. The Journal of Rheumatology, 2015. 35(5): p. 877-882. Strober, B., et al., Effects of etanercept on C-reactive protein levels in psoriasis
AC CE P
49.
and psoriatic arthritis. Br J Dermatol, 2008. 159(2): p. 322-30. 50.
Levine, J.S., D.W. Branch, and J. Rauch, The antiphospholipid syndrome. N Engl J Med, 2002. 346(10): p. 752-63.
51.
Greco, T.P., et al., Newer antiphospholipid antibodies predict adverse outcomes in patients with acute coronary syndrome. Am J Clin Pathol, 2009. 132(4): p. 613-20.
52.
Greco, T.P., et al., Oxidized-LDL/beta(2)-glycoprotein I complexes are associated with disease severity and increased risk for adverse outcomes in patients with acute coronary syndromes. Am J Clin Pathol, 2010. 133(5): p. 737-43.
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Mahler, M., et al., Autoantibodies to domain 1 of beta 2 glycoprotein 1: a promising candidate biomarker for risk management in antiphospholipid
Grundtman, C. and G. Wick, The autoimmune concept of atherosclerosis. Curr
RI
54.
PT
syndrome. Autoimmun Rev, 2012. 12(2): p. 313-7.
Opin Lipidol, 2011. 22(5): p. 327-34.
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Zhao, Q., Inflammation, autoimmunity, and atherosclerosis. Discov Med, 2009.
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8(40): p. 7-12.
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55.
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Table I Cardiovascular Disease Biomarkers Across Autoimmune Diseases
piHDL
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Coronary plaque
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Vessel rigidity
HLA haplotype DRB1
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Adhesion molecules ICAM and VCAM CRP
TNFα IL1/6 CD4+/CD28- T cells
T1D
Atherosclerosis: Presence of pro-inflammatory HDL increases risk of carotid plaque by 9 fold which enhances risk of atherosclerosis; 90% of SLE patients with plaque show significant levels of piHDL Atherosclerosis and Cardiac Events*: Patients with SLE and RA more likely to have high levels of CAC, a component of atherosclerotic plaques; CAC level is predictive of future cardiac event Atherosclerosis and Cardiac Events: Formation and rupture of plaque defines atherosclerosis; greater plaque burden yields increased risk for atherosclerosis; plaque burden is predictive of future cardiac event Atherosclerosis: the greater the stiffness, the higher the plaque burden and mean arterial pressure in SLE patients; also independently associated with inflammation, complement activation, and immune dysregulation components of atherosclerosis Cardiac Events: predictive of future cardiac event Thrombosis: positively associated with arterial thrombotic events; correlated with all-cause mortality and stroke in SLE patients; sign of abnormal complement activation; might indicate those with worse prognosis; Cardiovascular Disease-Associated Mortality: RA patients with two copies of this genetic marker demonstrate a 2-fold increase in cardiovascular disease-associated mortality Endothelial Dysfunction CVD: higher levels found in RA patients with CVD
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CAC
IMT C4d, etc.
Association
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Biomarker
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Disease
YKL-40
Adhesion molecules CRP Nitrotyrosine levels
Endothelial Dysfunction CVD: higher levels found in RA patients with CVD; predictor of CV risk in general population Endothelial Dysfunction CVD: higher levels found in RA patients with CVD Endothelial Dysfunction CVD: higher levels found in RA patients with CVD Endothelial Dysfunction CVD: higher levels found in RA patients with CVD; elevated levels found in peripheral blood linked to enhanced atherosclerosis Coronary Artery Disease: independently associated with coronary artery disease in T1D patients; may indicate disease presence, progression, and mortality risk CVD and Thrombosis: positively correlated with CVD in T1D patients CVD: positively correlated with CVD in T1D patients CVD: positively correlated with CVD in T1D patients
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VEGF Adipokines resistin and lepin
aPL syndrome
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CRP
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PsA
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aPLs such as anticardiolipin and IgG TNFα
anti-β2GPI
anti-oxLDL/β2GPI
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CVD: positively correlated with CVD in T1D patients Atherosclerosis: indicator of subclinical atherosclerosis; correlated with hypertension, increased arterial stiffness, and increased IMT relative to controls Atherosclerosis, Arterial Thrombosis, CVD: associated with aPL syndrome which shows increased risks for thrombosis, ischemic stroke, and plaque CVD: when TNFα-inhibiting therapeutics are administered continuously, disease severity and traditional CV risk factors (CRP, leptin, VEGF) in PsA patients decline Systemic Inflammation and Disease Severity: positively correlated with both in PsA patients Thrombosis and Insulin Resistance: upregulate adhesion molecules which promotes thrombosis and are positively correlated with insulin resistance Atherosclerosis, Systemic Inflammation, CVD: associated with plaque levels, inflammation levels, and risk of CVD Thrombosis, MI, and Stroke: positively associated with hypercoagulation, plaque, CV disease severity, and risks for future cardiovascular events Thrombosis, MI, and Stroke: positively associated with hypercoagulation, plaque, CV disease severity, and risks for future cardiovascular events
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IL1/6 Pulse wave velocity
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Abbreviations: SLE – systemic lupus erythematosus, piHDL – pro-inflammatory high density lipoproteins, CAC – coronary artery calcium, IMT – intima media thickness, RA – rheumatoid arthritis, I/VCAM – intercellular/vascular cell adhesion molecule, CRP – C reactive protein, IL1/6 – interleukins, TNFα – tumor necrosis factor α, T1D – Type I diabetes, SS - Sjögren’s Syndrome, aPLs – antiphospholipids, PsA – psoriatic arthritis, VEGF – vascular endothelial growth factor, anti-β2GPI – anti-β2 glycoprotein 1
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Cardiovascular disease (CVD) is a leading cause of premature mortality in patients with autoimmune diseases
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Biomarkers are essential to identify, monitor and stratify those at risk for CVD complications of autoimmune diseases
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Current areas of focus in CVD biomarker investigation include imaging modalities as well as biomarkers to reflect complement activation, endothelial dysfunction, and other aspects of inflammation and immune dysregulation
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