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Endothelial Dysfunction Is Associated with Activation of the Type I Interferon System and Platelets in Patients with Systemic Lupus Erythematosus

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Endothelial Dysfunction Is Associated with Activation of the Type I Interferon System and Platelets in Patients with Systemic Lupus Erythematosus Lupus RMD Open: first published as 10.1136/rmdopen-2017-000508 on 25 October 2017. Downloaded from ORIGINAL article Endothelial dysfunction is associated with activation of the type I interferon system and platelets in patients with systemic lupus erythematosus Helena Tydén,1 Christian Lood,1 Birgitta Gullstrand,1 Christoffer Tandrup Nielsen,2,3 Niels H H Heegaard,2,4 Robin Kahn,5 Andreas Jönsen,1 Anders A Bengtsson1 To cite: Tydén H, Lood C, ABSTRACT Gullstrand B, et al. Endothelial Objectives Endothelial dysfunction may be connected Key messages dysfunction is associated to cardiovascular disease (CVD) in systemic lupus with activation of the type I erythematosus (SLE). Type I interferons (IFNs) are central What is already known about this subject? interferon system and platelets in SLE pathogenesis and are suggested to induce both ► Patients with systemic lupus erythematosus (SLE) in patients with systemic lupus endothelial dysfunction and platelet activation. In this have increased risk for cardiovascular disease erythematosus. RMD Open (CVD) and both activation of type I interferons 2017;3:e000508. doi:10.1136/ study, we investigated the interplay between endothelial (IFNs) and platelets have been implicated in this rmdopen-2017-000508 dysfunction, platelets and type I IFN in SLE. Methods We enrolled 148 patients with SLE and 79 process. sex-matched and age-matched healthy controls (HCs). ► Endothelial dysfunction, an early step in the Prepublication history for ► Type I IFN activity was assessed with a reporter cell assay development of atherosclerosis, can be assessed this paper is available online. by non-invasive techniques as well as by surrogate To view these files please visit and platelet activation by flow cytometry. Endothelial markers, such as soluble vascular cell adhesion the journal online (http:// dx. doi. dysfunction was assessed using surrogate markers of org/ 10. 1136/ rmdopen- 2017- endothelial activation, soluble vascular cell adhesion molecule-1 and endothelial microparticles. molecule-1 (sVCAM-1) and endothelial microparticles 000508). What does this study add? (EMPs), and finger plethysmograph to determine Reactive Professor Niels H H Heegaard is Hyperaemia Index (RHI). ► Patients with SLE may have elevated type I IFN http://rmdopen.bmj.com/ deceased. Results In patients with SLE, type I IFN activity was activation leading to impaired endothelial function associated with endothelial activation, measured by high including patients with low disease activity. This article is based on work sVCAM-1 (OR 1.68, p<0.01) and elevated EMPs (OR 1.40, ► Patients with SLE and endothelial dysfunction have previously presented and p=0.03). Patients with SLE with high type I IFN activity activated platelets, which may contribute to an published as an abstract at the had lower RHI than HCs (OR 2.61, p=0.04), indicating elevated risk of CVD. Conference American College endothelial dysfunction. Deposition of complement factors of Rheumatology annual How might this impact on clinical practice? on platelets, a measure of platelet activation, was seen meeting 2015, title: Endothelial ► Analysing type I IFN signature, endothelial in patients with endothelial dysfunction. High levels of dysfunction in SLE -the role of function and platelet activation may add valuable platelets and type I interferons. sVCAM-1 were associated with increased deposition of information when evaluating cardiovascular risk in on September 23, 2021 by guest. Protected copyright. C4d (OR 4.57, p<0.01) and C1q (OR 4.10, p=0.04) on the individual patient with SLE. Received 2 June 2017 platelets. High levels of EMPs were associated with C4d Revised 17 September 2017 deposition on platelets (OR 3.64, p=0.03). Accepted 28 September 2017 Conclusions Endothelial dysfunction was associated SLE disease-related risk factors, including with activation of platelets and the type I IFN system. We steroid treatment, renal impairment and pres- suggest that an interplay between the type I IFN system, ence of antiphospholipid antibodies.4 Type I injured endothelium and activated platelets may contribute Interferons (IFNs) have been suggested to to development of CVD in SLE. be linked to CVD in SLE, as those cytokines may mediate imbalance between endothelial INTRODUCTION destruction and repair, leading to endothelial Systemic lupus erythematosus (SLE) is a dysfunction, an early stage in atherosclerosis systemic autoimmune disease that predom- development.5 In addition to their role in 6 7 For numbered affiliations see inately affects women of reproductive age. CVD and SLE pathogenesis, platelets have end of article. An increased prevalence of cardiovascular an impact on endothelial function.8 The disease (CVD) in SLE is well described. To aim of this study was to take both type I IFN Correspondence to Dr Helena Tydén; some extent this increase may be explained activity and platelet activation into account helena. tyden@ med. lu. se, by traditional CVD risk factors, such as when investigating endothelial dysfunction in helena. tyden@ skane. se smoking, dyslipidaemia and diabetes,1–3 and SLE. Tydén H, et al. RMD Open 2017;3:e000508. doi:10.1136/rmdopen-2017-000508 1 RMD Open RMD Open: first published as 10.1136/rmdopen-2017-000508 on 25 October 2017. Downloaded from Endothelial dysfunction is a state of impaired endothe- In brief, this study found that patients with SLE with lial dependent vasodilatation that also consists of endo- an activated type I IFN system had impaired endothelial thelial activation, a proinflammatory state with decreased function and the patients with endothelial activation had endothelial anticoagulant ability.9 10 Several methods may increased platelet activation. Thus, we suggest that acti- be used to assess endothelial dysfunction. Serum levels of vation of platelets and platelet-endothelium interactions endothelial derived markers, such as soluble vascular cell may contribute to impaired endothelial function and the adhesion molecule-1 (sVCAM-1), is elevated as a conse- development of CVD in SLE. quence of endothelial activation and dysfunction.11 12 Furthermore, endothelial microparticles (EMPs), subcel- MATERIALS AND METHODS lular vesicular fragments that shed from endothelial cells Patients and controls 13 in response to certain stimuli, have been reported to Patients with SLE (n=148) as well as age-matched and 14 15 correlate with endothelial dysfunction and endothe- sex-matched healthy controls (HCs, n=79) were recruited 13 lial damage. Non-invasive techniques to assess endothe- at the Department of Rheumatology, Skåne University lial dysfunction have been developed, with flow mediated Hospital, Lund, Sweden. An overview of the clinical char- dilatation (FMD) measurement of the brachial artery acteristics of the 148 patients with SLE and 79 healthy 9 considered as the gold standard. However, the method volunteers is presented in tables 1 and 2. Median disease is complex and operator-dependent. Abnormal pulse duration of the patients with SLE was 11 years (range wave amplitude (PWA) in peripheral arteries as a marker 0–46). Disease activity in the patients with SLE was of atherosclerosis and predictor of cardiovascular events assessed using Systemic Lupus Erythematosus Disease 16 17 may be used as an alternative. Peripheral artery tonom- Activity Index 2000 (SLEDAI-2K).26 Median SLEDAI-2K etry (PAT) using a device called EndoPAT has been devel- Score in the patients with SLE was 1.5 (range 0–18) and oped to measure PWA in finger arteries and is an easy, SLEDAI-2K Scores are demonstrated in table 2. All but investigator independent, method to assess endothelial two patients with SLE fulfilled at least four American dysfunction. A linear relationship between endothelial College of Rheumatology (ACR) 1982 classification dysfunction measured with FMD and EndoPAT has been criteria for SLE.27 The last two patients fulfilled three 18 demonstrated previously. ACR criteria, had a clinical SLE diagnosis with at least Type I IFNs are key cytokines in the pathogenesis of SLE two organ manifestations characteristic of SLE, autoim- with a number of regulatory effects on both innate and mune phenomena and no other diagnosis that could 19 adaptive immunity and have been suggested to mediate better explain the symptoms. The median Systemic increased endothelial progenitor cell (EPC) apoptosis Lupus International Collaborating Clinics/ACR Damage and the differentiation of circulating angiogenic cells Index (SLICC/ACR-DI) Score of the patients with SLE (CACs) to non-angiogenic cells. This imbalance between was 0 (range 0–8). The participants completed question- vascular damage and repair may cause endothelial naires concerning smoking, general health and medica- http://rmdopen.bmj.com/ dysfunction in SLE. In addition, type I IFNs affect the tion. All subjects were examined by a rheumatologist at capacity of EPC/CAC to produce proangiogenic mole- inclusion into the study. Traditional cardiovascular risk cules which can be restored by blocking type I IFNs in factors; age, gender, hypertension (systolic blood pres- 5 vitro. In SLE, type I IFNs have been demonstrated to sure equal or higher than 140 mm Hg at the time point exert their effects on EPC/CACs through downregu- of blood sampling or hypertensive treatment due to lation of the proangiogenic interleukin (IL)−1 signal- high blood pressure) and plasma low density lipoprotein ling pathways and by affecting the inflammasome and (LDL) cholesterol levels were analysed. History of cere- 20 21 promoting
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