Accelerated Atherosclerosis in Autoimmune Rheumatic Diseases Prof. Andrea Doria

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1 Accelerated Atherosclerosis Andrea Doria Division of Rheumatology University of Padova 1 Endothelial Dysfunction Fatty-Streak Formation Endothelial Leukocyte Endothelial Leukocyte permeability migration adhesion adhesion Formation of an advanced lesion Smooth Adherence Adherence muscle Foam cell T-cell and and entry of migration formation activation aggregation leukocytes of platelets Unstable fibrous plaques Macrophage Formation of Fibrous cap accumulation necrotic core formation Russel Ross N Engl J Med 1999;34: Plaque rupture Thinning of fibrous cap Hemorrhage from plaque microvessels 2 Pathogenetic Steps in Atherosclerosis Monocyte Vessel lumen LDL Adhesion molecules MCP-1 P-D LDL Endothelium Cytokines oxidate LDL Growth factors Cell proliferation Macrophage Breakdown of fibrous cup Intima Ross R. N Engl J Med 1999;34: Foam cell MMP Matrix degradation 3 The screen versions of these slides have full details of copyright and acknowledgements 1

2 Triggers and Common Pathway in Atherosclerosis Infections CV risk factors Chronic inflammatory diseases Innate/adaptive immunity Endothelial dysfunction Atherosclerosis/inflammat ion Vessel lumen Endothelium Intima 4 Key Features of Innate and Adaptive Immunity in Atherogenesis Innate Immunity Rapid immune response to pathogen Antigen recognition driven by pattern recognition receptors which bind to highly conserved structures expressed by pathogens Effectors Phagocytes Pattern recognition receptors Pentraxines (CRP, PTX3) Complement Cytokine (TNFα, IL-1, IL-6) Chemokines (MCP-1) Inflammation Atherosclerosis Adaptive Immunity Require three to five days to mature Antigen recognition driven by T and B cell receptors; Very specific antigen recognition Effectors T and B cell T and B cell receptors Cytotoxic T cell Antibodies Cytokine (TNFα, IL-2, INFγ) Chemokines 5 Chronic Inflammatory Diseases CV Risk Factors Infectious Agents Innate immunity 6 The screen versions of these slides have full details of copyright and acknowledgements 2

3 Immunocytochemistry for CRP Distribution Within the Atherosclerotic Plaque m apl 7 Odds Ratios for Coronary Heart Disease Among 2459 Patients with Coronary Heart Disease and 3969 Controls Danesh, J. et al., N Engl J Med 24;35: Unstable Carotid Plaque (CARS) Macrophages Lymphocytes Pauletto P, Circulation 2; 12(7): The screen versions of these slides have full details of copyright and acknowledgements 3

4 An Unusual Subset of T-Cells, CD4+CD28 null, Is Clonally Expanded in the Peripheral Blood and Infiltrates Coronary Plaques in UA CD4+ CD28 null T cells (%) CD4 + CD28 n u ll T cells expansion in UA 4 35 P < Stable Angina Unstable Angina Liuzzo G, Circulation 1999; 1: Infiltration of selected CD4 + CD28 n u ll T cells clones into the unstable plaque L = Left anterior descending coronary artery R = Right coronary artery, culprit lesion Liuzzo G, Circulation 2; 11: CD4+CD28 null Lymphocytes Undergo clonal proliferation Form long-lived clonal population Produce IFN-γ high levels (Liuzzo G, Circulation 1999; 1: ) Coexpress the CD57 NK cell marker Have cytolytic activity (Nakajima T, Circulation 22; 15: 57-5; Nakajima T, Circ Res 23; 93: ; Nakajima T, Circulation 22; 15: 57-5) Are autoreactive Enhanced number with increasing age in the blood of healthy subjects (Warrington KJ Blood 23;11:3543-9) 11 Frequency of CD4+CD28 - T Cells in 87 RA and 3 Control Subjects Gerli R, et al., Circulation 24,19: The screen versions of these slides have full details of copyright and acknowledgements 4

5 Common Carotid IMT in RA Patients Subdivided According to the Presence or Absence of CD4+CD28- Cell Expansion Common carotid IMT (mm) Controls Gerli R, et al., Circulation 24,19: * * All RA CD4+CD28+ CD4+CD28-13 Atherosclerosis and Autoimmunity Anti-oxLDL Anti-β2GPI Anti-HSP6/65 Anti-ECA Anti-HDL Anti-APO A-1 Anti-LPL Doria A, Sherer Y, Meroni PL, Shoenfeld Y. Rheum Dis Clin N Am 25; 31: Oxidized LDL and other lipoproteins can be actively taken up by scavenger receptor mediated endocytosis, transforming macrophages into the so called foam cells Some anti-oxldl can enhance oxldl uptake by macrophages through the involvement of the Fcγ receptors rather than via the usually employed scavenger receptor favouring foam cell formation and macrophage activation oxldl Anti-oxLDL 15 The screen versions of these slides have full details of copyright and acknowledgements 5

6 Anti-oxLDL and Atherosclerosis Raised levels in some conditions linked to coronary artery disease in humans Lehtimaki T, et al., Arterioscl. Thromb. Vasc. Biol 19, 23-7, 1999 Maggi E, et al., Arterioscler Thromb 14, , 1994 Saloen J.T., et al., Lancet 339, 883-7, 1992 Meraviglia MV et al., Stroke 22, 33: George J, et al., Immunol Lett 1999;68:263-6 Immunization with oxldl of animals results in suppression rather than aggravation of early atherogenesis Palinski W. et al., Proc Natl Acad Sci USA 92, , 1995 George J, et al., Atherosclerosis 138, , 1998 Ameli S, et al., Arterioscler Thromb Vasc Biol 16, 174-9, 1996 Anti-oxLDL mabs inhibit uptake of oxldl by macrophages Show PX, et al., Atherosclerosis, Thrombosis & Vascular Biology 21, 1: 333-9, Anti-oxLDL and Atherosclerosis Protective Pathogenetic Help to clear the high levels of oxldl Aid the uptake of oxldl by macrophages turning them into foam cells within the atherosclerotic plaques IgM anti-oxldl IgG anti-oxldl 17 Antiphospholipid Antibodies Generally they are directed to phospholipids binding proteins (β 2 glycoprotein I, prothrombin, etc.) Detected by different tests as: Lupus anticoagulant, Anticardiolipin antibodies Anti β2gpi Anti prothrombin Anti ethanolamine Anti annexin Anti phospholipids Major cause of thromboembolic disorder in patients with autoimmune diseases and otherwise healthy subjects (antiphospholipid syndrome) 18 The screen versions of these slides have full details of copyright and acknowledgements 6

7 The Primary Structure of Human β2gpi and Location of Attachment Sites for Oligosaccharide Chains Characters of amino acid residues Positively charged Negatively charged Polar(-NH2) Polar(-OH,-SH) Hydrophobic glycine 19 2 β2gpi Adhered on Endothelial Cells Is a Target for Anti-Phospholipid Antibodies β 2GPI adhesion to endothelium in vivo (McIntyre 1993, La Rosa 1994) β2gpi β 2GPI binding to endothelial monolayers in vitro (Del Papa 1995, 1997, 1998) β 2GPI binds endothelium through the PL-binding site located at the fifth domain and through annexin II (Del Papa 1998; Keying 2) Endothelium ++ + β2gpi 21 The screen versions of these slides have full details of copyright and acknowledgements 7

8 - -- Accelerated Atherosclerosis Two Step Complex Formation Between OxLDL and β2gpi apob1 Free β 2GPI Intermediate complexes Stable complexes oxldl ph7.4 oxldl ph7.4 oxldl ph7.4 + Mg 2+ +heparin Matsuura E, et al., Lupus 25; 14: ph1 + Mg 2+ +heparin Electrostatic and dissociable complexes, formed with β 2GP ligands (ω -carboxyl), such as oxlig-1 and oxlig-2 (Schiff base etc.) Stable complexes (i.e., Schiff base adducts), formed with ω -aldehydes 22 Serum OxLDL/β2GPI Complexes May Be a Marker of Vascular Inflammation Disease Inflammation Oxidative Stress Lipid Modification Antibody Clinical manifestation SLE APS Chronic Autoimmune Vasculitis ++++ OxLDL/β2GPI IgG/IgM Premature Atherosclerosis + CVD SSc? +++ OxLDL/β2GPI IgG/IgM CVD Atherosclerosis DM-2 Infectious Endocarditis Chronic Hyperglycemia Blood Infection (Sepsis) OxLDL/β2GPI OxLDL/β2GPI IgM -- Premature Atherosclerosis + CVD No Atherosclerosis Healthy Matsuura E, et al., Lupus 25; 14: Age-related + risk Factors 23 The Role of β2gpi in Atherogenesis β 2GPI oxldl Anti-β 2GPI Da Koike T, The screen versions of these slides have full details of copyright and acknowledgements 8

9 Immunolocalization of β 2 GPI (Apolipoprotein H) in Human Atherosclerotic Plaques: Potential Implications for Lesion Progression George et al., Circulation 9 9 :2227, 1999 A and B rabbit anti-β 2GPI antibody C, normal rabbit IgG D, hematoxylin- eosin E, anti-cd4 F, anti-cd8 25 Immunization with Human β2 Glycoprotein I In LDL-receptor-d eficient mice or Apo-E knock-out mice immunization with β 2GPI enhances atherosclerotic lesions which contain abundant CD4+ cells George J et al., Circulation 1998; Afek A et al., Pathobiology 1999 T cell depletion impairs reproduction of the experimental model!! The transfer of lymphocytes from mice immunized with β 2GPI to mice of similar genetic background increases atherosclerotic lesions compared to those occurring in animals tranferred with lymphocytes from control mice 26 Antiphospholipid Antibodies in Patients with Clinical and Subclinical Atherosclerosis The presence of antiphospholipid antibodies was found to be a risk factor for various manifestations of coronary artery disease such as angina, myocardial infarction or cardiac death, as well as being associated with subclinical atherosclerosis Vaarala O et al., Circulation 1995, 91:23; Sherer Y, Cardiology 21, 95: 2 Sherer Y et al., Am J Cardiology 2, 86: Vaarala O et al., Thromb Haemost 1996, 75:456 Shoenfeld Y, et al., Ann.Med. 2, 1:37-4 Glueck et al., Am J Cardiol :149; Nityanand S et al., J Intern Med 1995, 238:437 It has also been shown that patients with primary antiphospholipid syndrome have a high prevalence of increased carotid intima-media thickness or plaque Ames PRJ, et al., Lupus 22; 11: G. Medina, et al., Ann Rheum Dis 23;62:67-61 PG Vlachoyiannopoulos et al., Rheumatol23;42: The screen versions of these slides have full details of copyright and acknowledgements 9

10 Reduction of Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice by Passive Administration of Antiphospholipid Antibody In contrast to earlier studies of apl which were specific for oxidized forms of LDL, FB1 cross-reacted with both native LDL and oxldl In vivo, passive administration of FB1 significantly reduced plaque formation in atherosclerosis-prone LDLR(-/-) mice These results indicate that some apl may play a protective role in atherogenesis Nicolo D, et al., Arthritis Rheum 23; 48: Human HSP6 Intracellular chaperone protein Expressed on the surface of stressed cells Human HSPs are expressed on endothelial cells in response to stressors like hypertension, smoking, lipoproteins, etc. HSPs offer a target for autoimmunity under such circumstances HSP6 shows high inter-species homology 29 Anti-Heat Shock Protein (HSP) 6/65 Antibodies Patients with high levels of anti-hsp65 were found to be at increased risk of subsequent cardiovascular events and cardiovascular mortality SoRell R. Circulation 16: , 22 Xu Q, et al., Circulation 1: 1169, 1999 Subjects with sonographic evidence of carotid atherosclerotic lesions had significantly elevated levels of anti-hsp65 compared with controls Xu Q, et al., Lancet 341: 255, 1993 Immunization of animals with mycobacterial or recombinant antigen causes atherosclerotic lesions (rabbits, C57BL/6 mice fed with high cholesterol diet, or LDL receptor deficient mice) George J, et al., Arterioscler Thromb Vasc Biol, 19:55-51,1999 Xu Q, et al., Arterioscl Thromb 12: 789, 1999 Afek A, et al., J Autoimmun 14: 115, 2 3 The screen versions of these slides have full details of copyright and acknowledgements 1

11 Enhanced Atherosclerosis and Associated Factors in ARD Disease Evidence for enhanced ATS Factors involved in enhanced ATS RA SLE APS SSc Prevalence of CAD, increased extent of subclinical ATS Prevalence of CAD, increased extent of subclinical ATS Prevalence thrombosis, increased extent of subclinical ATS, apls are prevalent in patients with macrovascular disease, apls predict future CVD in the general population Prevalence of macrovascular disease, few studies on ATS Prevalence of classic risk factors for ATS, drugs used for treatment Prevalence of classic risk factors for ATS, corticosteroid therapy, long disease duration Animals models support a proatherogenic role of apl Oxidative stress, antiendothelial cell antibodies PSV SS Increased extent of subclinical ATS in WG; Not studied in other diseases Not studied Shoenfeld Y, Gerli R, Doria A, et al., Circulation 25; 112: Enhanced inflammation and excessive vascular remodelling Unknown 31 Marson P. et al., Reumatismo 24; 56: The Prevalence of Coronary Artery Disease Is Higher in RA Patients than in General Population RA patients have a 2-3 fold increase in rates of MI compared to the general population Solomon DHM, et al., Circulation 23;17: Del Rincon ID, et al., Arthritis Rheum 21; 44: They are more likely to experience silent ischaemia and sudden cardiac death Maradit-Kremers H, et al. Arthritis Rheum 25; 52: The screen versions of these slides have full details of copyright and acknowledgements 11

12 Prevalence of Coronary Artery Disease (CAD) in Three Cohort of SLE Patients and in Women of Framingham Offspring Study Baltimore (1992) Toronto (1995) Pittsburgh (1997) Framingham Offspring Study Patients, N Prevalence of CAD 8,3% 1% 6,7% 1,6% Baltimore: Petri M, et al., Am J Med 1992; 93: Toronto: Abu-Shakra M, et al., J Rheumatol 1995; 22: Pittsburgh: Manzi S, et al., Am J Epidemiol 1997; 145: Incidence Rates of MI per 1 Person-Years in 498 Women with SLE, University of Pittsburgh, and 2,28 women, Framingham Offspring Heart Study, Age (years) Rate SLE 95% CI Rate Framingham 95% CI Rate ratio 95% CI Manzi S, et al., Am J Epidemiol 1997; 145: Risk Factors for Atherosclerosis in SLE The evaluation of risk factors for clinical atherosclerosis is difficult in SLE because of the low number of observed cardiovascular events due to the low prevalence of the disease The study of subclinical atherosclerosis has the advantage of providing a higher number of lesions leading to a more suitable evaluation of risk factors 36 The screen versions of these slides have full details of copyright and acknowledgements 12

13 Non-Invasive Techniques for the Detection of Subclinical Atherosclerosis Brachial flow mediated vasodilatation (BFMV) Pulse-Wave Velocity (PWV) Carotid Color Doppler Ultrasonography (US) Electron Beam Computed Tomography (CT) Scintigraphy (Thallium-21) Single Photon Emission Computed Tomography (SPECT) Thallium-21 Dual Isotope Myocardial Perfusion Imaging (DIMPI) 37 Duplex Ultrasonography Intima-media thickness (IMT) of common carotid artery 38 Evidence of Increased IMT in Patients with Rheumatoid Arthritis Wallberg S, et al., J Rheumatol 21;28: Kumeda Y, et al., Arthritis Rheum 22;46: Park Y-B, et al., Arthritis Rheum 22;46: Alkaabi JK, et al., Rheumatology 23;42:292-7 Del Rincon, et al., Arthritis Rheum 23;48: Gonzales C, et al., Medicine 23;82:47-13 Nagata M, et al., Arthritis Rheum 23;48: The screen versions of these slides have full details of copyright and acknowledgements 13

14 Traditional risk factors Age Sedentary life style Diabetes Dyslipidaemia Smoking Hypertension R.F. Drugs CysA Steroids HC MTX CIC Proinflammatory cytokines Cellular dysfunction Acute-phase Adhesion reactants molecules Chronic Inflammation Homocysteine Prothrombotic state Similarities between Atherosclerosis RA C-reactive protein Adhesion molecules Neoangiogenesis (UA) Macrophage activation TNF-α Metallopr. Expression IL-6 Mast cell activation B-cell activation Autoantibodies (oxldl, HS) Rheumatoid factor T-cell activation sil-2 receptor CD3+ DR+ CD4+ CD28- CD4+ IFN-γ Th1/Th2 balance or (UA) (UA) (UA) (UA) (UA) Th1 or 41 Th1 Patients n. Mean age (years) Female % White% Previous CVD % Plaque definition Plaque % Mean IMT (mm) Risk factor evaluation Carotid Ultrasound Studies in SLE Manzi et al. (1999) mm IMT (mean±sd) >5% than surrounding area Roman 4 MJ, et 65al. N Eng 38 J Med 23; 37349: ±.14.66±.15.6±.14 Cross sectional 1, 4 1, 2 1, 8, 6, 4, 2 Svenungsson et al. (21) SLE cases ±.16.67± Not reported SLE IMT>1 patients mm Cross sectional SLE controls p<.1 26 Roman et al. (23) 197 ~5 12 >5% than IMT>1.3 Healthy surrounding subjects mm area.61±.16 Cross sectional Shoenfeld Y, Gerli R, Doria A, et al. Circulation 25; 112: Doria et al. (23) ±.15 Prospective Selzer et al. (24) >5% than surrounding area 32.71±.1 Cross sectional 42 The screen versions of these slides have full details of copyright and acknowledgements 14

15 Traditional and Other Metabolic Risk Factors for ATS Age Sex Hypercholesterolaemia Hypertension Obesity in SLE Diabetes Sedentary life style Cigarette smoking Family history for CVD Hypertryglyceridaemia Mean number of CV risk factors per person Premature menopause Hyperhomocysteinaemia in SLE Insulin SLE patients resistance >>> General population Petri M, et al., Medicine (Baltimore) 1992; 71: ; Bruce IN, et al., Arthritis Rheum 23; 48: ; EL-Magadmi M, et al., J Rheumatol 23; 48: Cardiovascular Risk in Lupus SLE Overall Risk of CHD General population Low Traditional risk factors High Wajed et al., Rheumatol 24; 43: 7 44 Novel Risk Factors for Atherosclerosis Markers of inflammation Acute-phase proteins CRP Serum amyloid A Adhesion molecules ICAM-1 P selectin E selectin Cytokines IL-6 TNFα Immunological factors Adaptive immunity Anti-β 2GPI Anti-oxLDL Anti-HSP-65 Innate immunity Toll-like receptor (TLRs) TLR4 Scavenger receptors (SR) SR-A CD36 Lipoproteins and modified lipids Lipoprotein (a) Oxidized LDL Small, dense, LDL Abnormal coagulation factors Fibrinogen PAI-1 Homocysteine 45 The screen versions of these slides have full details of copyright and acknowledgements 15

16 CRP and Subclinical Atherosclerosis in SLE CRP was associated with plaques at univariate, but not at multivariate analysis Selzer F, et al., Arthritis Rheum 24; 5: CRP was not associated with plaques Roman MJ, et al., N Eng J Med 23; 349: Cross-Sectional Studies on the Relationship Between Autoantibodies and Atherosclerosis (ATS) in SLE Patients Zampieri S, Doria A, et al., Ann N Y Acad Sci 25; 151: Subclinical Atherosclerosis in SLE: Study Design Traditional risk factors Treatment during follow-up Carotid ultrasound examination 78 SLE pts T 5 year follow-up T1 SLE clinical and laboratory features SLE disease activity (ECLAM) SLE damage index (SLICC DI) Novel predictors: CRP, anti-oxldl, anti-β 2GPI, and anti-hsp65 Doria A, et al., Ann Rheum Dis 23; 62: The screen versions of these slides have full details of copyright and acknowledgements 16

17 U/ml6 Correlation Between M-IMT and IgG Anti-oxLDL Levels IgG anti-oxldl levels at T r=.344, p=.2,,1,2 M-IMT Doria A, et al., Ann Rheum Dis 23; 62: ,3 mm 49 Conclusions The IgG role anti-oxldl of anti-β2gpi, may anti-hsp65 play a role and CRP seems in to the be masked accelerated by some atherosclerotic disease-related process features observed particularly in SLE prednisone patients cumulative dosage and renal involvement SLE-Related Risk Factors for Atherosclerosis SLE phenotype SLE activity Severe/mild SLE Glomerulonephritis Arthritis apl syndrome Other manifestations Doria A, et al., Ann Rheum Dis 23; 62: Disease duration Treatment Corticosteroids Immunosuppressants Others 5 Questions Which Should Be Addressed: 1) Who are at highest risk for accelerated atherosclerosis? Severe or mild SLE patients? Patients with renal involvement or those with skin or joint manifestations? 2) Are corticosteroids pro or anti-atherosclerotic? 51 The screen versions of these slides have full details of copyright and acknowledgements 17

18 Correlates of Accelerated Atherosclerosis in SLE Roman MJ, et al., N Eng J Med 23; : st Multivariate analysis Traditional risk factors Age Menopausal status Systolic BP Total cholesterol LDL cholesterol 2nd Multivariate analysis SLE related features Age at diagnosis Longer SLE duration SLICC damage index Pulmonary hypertension Anti-RNP Anti-Sm 5-yr daily dose of PDN Cyclophosphamide use Hydroxychloroquine use Significant in univariate and multivariate analyses 52 Severe or Mild SLE Patients: Who Are at Highest Risk for Accelerated Atherosclerosis? In Roman s study, patients with less severe disease were older than those with more severe disease The higher prevalence of plaque in the former group of patients could not be related to milder disease, but to age itself, a factor not considered by the authors in the multiple regression analysis for disease-related factors Doria A, et al., N Eng J Med 24; 35: Risk Factors for Carotid Plaques in SLE Doria A et al., Ann Rheum Dis 23; 6 2 : Multivariate analysis Traditional risk factors Age Hypertension Hypercholesterolemia SLE related features Renal involv. at T ECLAM >2 at T PDN 4 gr Azathioprine Significant in univariate and multivariate analyses 54 The screen versions of these slides have full details of copyright and acknowledgements 18

19 78 SLE Patients Traditional risk factors Lipoprotein subclasses SLE variables Novel risk factors 1 8 % Groups: A B C <18 g g >38 g Prednisone cumulative intake Doria A et al., Arthritis Rheum 24; 5: S191-S Mean (±SD) Prednisone (PRD) Cumulative Dosage in Patients with and Without Carotid Plaque Patients with plaque Patients without plaque * Adjusted for traditional risk factors including BP and lipoprotein subclasses Doria A et al., Arthritis Rheum 24; 5: S191-S Mean (±SD) Prednisone (PRD) Cumulative Dosage in Patients with and Without Carotid Plaque grams of PRD ±5.2 p=n.s. 29.3±2. Patients with plaque Patients without plaque PRD adjusted* * Adjusted for traditional risk factors and renal involvement Doria A et al., Arthritis Rheum 24; 5: S191-S The screen versions of these slides have full details of copyright and acknowledgements 19

20 The Bimodal Mortality Pattern of SLE Urowitz MB, et al., Am J Med 1976; 6 : % Active SLE CHD Early mortality Late mortality Years After Diagnosis 58 Long-Term Prognosis in SLE Doria A, et al., Am J Med 26; : 7-6 % Years After Diagnosis Urowitz et al., Am J Med 1976 Doria et al., Am J Med Long-Term Prognosis in SLE Doria A, et al., Am J Med 26; : Mild disease 72 % 6 Severe disease Years After Diagnosis 6 The screen versions of these slides have full details of copyright and acknowledgements 2

21 Maximum effort should be made: To adequately treat severe lupus manifestations, particularly glomerulonephritis, using the lowest possible dosage of corticosteroids associated with corticosteroid sparing therapy To manage modifiable traditional risk factors for ATS, first of all hypertension and hypercholesterolemia, as quickly as possible Take Home Message To consider the use in these patients of low-dose aspirin, hydroxychloroquine, and ACE inhibitors 61 Triggers and Common Pathway in Atherosclerosis Infections CV risk factors Chronic inflammatory diseases Innate/adaptive immunity Endothelial dysfunction Vessel Lumen Endothelium Atherosclerosis/inflammat ion 62 Intima The Role of the Endothelium in the Maintenance of Vascular Homoeostasis Vasodilation Anti-inflammatory Anti-thrombotic Anti-coagulant Pro-fibrinolytic Vasoconstriction Pro-inflammatory Pro-thrombotic Pro-coagulant Anti-fibrinolytic Endothelium Vessel Lumen Intima 63 The screen versions of these slides have full details of copyright and acknowledgements 21

22 Assessment of Endothelial Function Circulating markers of vascular wall inflammation Endothelial vasomotor testing (endothelial stress test) Intra-arterial infusion of specific endotheliumdependent vasodilators (coronary microcirculation, brachial or femoral circulation) Ultrasound measurement of brachial artery reactivity to shear stress (upper arm occlusion) Lerman, A. et al., Circulation 25;111: Ultrasound Assessment of Endothelial- Dependent Flow-Mediated Vasodilation of Brachial Artery 65 Evidence of Endothelial Dysfunction as Predictor of CV Events Lerman, A. et al., Circulation 25;111: The screen versions of these slides have full details of copyright and acknowledgements 22

23 Endothelial-Dependent FMV of Brachial Artery in Patients with ARD Endothelial dysfunction was reported in patients with: Rheumatoid arthritis Bergholm R et al., Arterioscler Thromb Vasc Biol 22;22: Hurlimann D et al., Circulation 22;16: Van Doornum S et al., Arthritis Rheum 23;48:72-8 Systemic lupus erythematosus Lima et al., J Rheumatol 22; 29: 292 El-Magadmi et al., Circulation 24; 11: 399 Johnson SR et al., Lupus 24; 13:59-3 Primary antiphospholipid antibody syndrome Mercanoglu F, et al., Int J Clin Pract 24; 58: 13-7 Sjıgren syndrome Pirildar T, et al., Rheumatol Int 25; 25:536-9 Primary systemic vasculitis Booth AD, et al., Circulation 24; 19: ; Ozdemir R, et al., Am J Cardiol 24; 94: ; Raza K, et al., Circulation 2; 12: 147-2; Filer AD, et al., Ann Rheum Dis 23; 62: Why Patients with Autoimmune Rheumatic Diseases Have a Diffuse Endothelial Dysfunction? 68 Vascular Endothelium at the Site of the Primary Inflammatory Response and at Distant Sites Local inflammation Distant effects Leucocyte recruitment Systemic TNF-α Systemic TNF-α /CRP etc. Endothelial dysfunction Stromal/endothelial interactions Buckley, C. D. et al., Rheumatology 25 44: The screen versions of these slides have full details of copyright and acknowledgements 23

24 Acknowledgments Anna Ghirardello Luca Iaccarino Sandra Zampieri Silvia Arienti Maria Elisa Rampudda Nicola Bassi Yheuda Shoenfeld Paolo Pauletto Pier Luigi Meroni Roberto Gerli Angela Tincani 7 71 The screen versions of these slides have full details of copyright and acknowledgements 24