07-03-2011 Department of Rheumatology, Rigshospitalet Lupus as a risk factor for cardiovascular disease SØREN JACOBSEN Department Rheumatology, Rigshospitalet Department of Rheumatology, Rigshospitalet Søren Jacobsen Main sponsors: Disclaimer: • Gigtforeningen • Novo Nordisk Fonden • Rigshospitalet • • • • Novo Nordisk A/S Active Biotech AB GlaxoSmithKline Pharma Roche 1 07-03-2011 Department of Rheumatology, Rigshospitalet Department of Rheumatology, Rigshospitalet Increased mortality in SLE • Standardized mortality ratios in major clinical studies of SLE • • • • SLICC cohort, 1970-2001 Denmark, 1975-95 Canada • 1970-77 • 1978-85 • 1986-94 10.1 4.8 3.3 Lupus nephritis, 1975-2007 6.8 (95% CI 4.9-9.4) • 1971–79 • 1980–89 • 1990–95 2.4 (95% CI 2.3-2.5) 4.6 (95% CI 3.8-5.5) 9.0 (4.7–17.1) 6.2 (4.0–9.5) 6.6 (3.1–13.8) • • • Jacobsen et al, Scand J Rheumatol 1999 Bernatsky et al, Arthritis Rheum 2006 Faurschou et al, Arthritis Care Res 2010 2 07-03-2011 Department of Rheumatology, Rigshospitalet The bimodal mortality pattern of SLE Urowitz et al. Am J Med 1976 Department of Rheumatology, Rigshospitalet CVD is among the leading causes of death in SLE • Bernatsky et al, A&R 2006 • 9,547 patients 1255 deaths • CVD 313 (25%) • Jacobsen et al, Scand J Rheumatol 1999 • 513 patients 122 deaths • CVD 36 (30%) • Infections 25 (22%) • Malignancies 9 (8%) • Chambers, Rheumatology 2009 • 232 patients 44 deaths • Infections 11 (25%) • CVD 9 (20%) • Malignancies 8 (18%) SMR: 1.7 (1.5–1.9) 3 07-03-2011 Department of Rheumatology, Rigshospitalet Increased CVD mortality in SLE due to • Increased cardiovascular morbidity • Increased case fatality • • (Manzi Am J Epid 1997) Stroke No Myocardial infarction ? Department of Rheumatology, Rigshospitalet Factors that may be associated with development of CVD in SLE • Standard risk factors • • • • • • • Disease related factors • • • • • • • • Age Hypertension Hyperlipidemia Hyperglycemia Smoking Obesity Systemic inflammation Autoantibodies Circulating immune complexes Activated complement products Nephritis Inflammation-associated lipid profile Inflammation-associated insulin resistance Hahn NEJM 2003 Adverse and protective effects of drugs • • • • Hydroxychloroquine (HCQ) Prednisolone Biologics NSAIDs 4 07-03-2011 Department of Rheumatology, Rigshospitalet Atherosclerosis – early stage Impaired endothelial function • Patients with CVD • • Reduced FMD CVD-free patients • FMD reduced or normal NO-dependent arterial vasodilation -Flow mediated vasodilation (FMD) -Nitroglycerin mediated (NMD or FID) Department of Rheumatology, Rigshospitalet Atherosclerosis - intermediate stage Increased • Intima-media thickness • • Arterial stiffness Pulse wave velocity 5 07-03-2011 Department of Rheumatology, Rigshospitalet Atherosclerosis - plaques Increased • coronary artery calcifications on CT • plaque formation on ultrasound Department of Rheumatology, Rigshospitalet Atherosclerosis - advanced plaques • • • Vulnerable Ulcerated Ruptured 6 07-03-2011 Department of Rheumatology, Rigshospitalet CASE Female patient with SLE • Age 42: • Age 43: Arthralgias, Raynaud and photosensitivity Pleuritis, thrombopenia, anti-DNA and ANA • HCQ and prednisolone • Age 44: Proteinuria Renal biopsy: proliferative GN (class IV) • HCQ stop, AZA and prednisolone • Age 46: Hypertension, angina, clearance, creatinine OK • Diuretic and ACE-inhib, cont. AZA and prednisolone • Age 49: Myocardial infarction • ASA • Age 52: Cutaneous vasculitis • Prednisolone and cont. AZA • Age 55: Death due to myocardial infarction Department of Rheumatology, Rigshospitalet CASE Another female patient with SLE – but very different story • Age 30: Raynaud, leukopenia, proteinuria, antiDNA ANA, lupus anticoagulant, hypertension Renal biopsy: membranous GN (class V) • Cyclophosphamide and prednisolone • Age 32: Thrombopenia • Resolved on prednisolone • Age 33: Low grade activity in nephritis • Cyclosporin A Project: normal IMT, no plaques, low FMD • Age 35: Well-being, no signs of active disease Sudden death due to myocardial infarction during hiking vacation • No autopsy 7 07-03-2011 Department of Rheumatology, Rigshospitalet Findings in coronary arteries N=50 Normal arteries 5 Normal arteries + thrombosis 11 Aneurysms 5 Arteritis 7 Atherosclerosis 22 Poor agreement between coronary angiography and myocardial perfusion scintigraphy Nikpour, Lupus 2011 • fx 14 (58%) out of 24 having perfusion defects and normal angiograms Microcirculation? Department of Rheumatology, Rigshospitalet Anti-phospholipid antibodies and CVD The Hopkins Lupus Cohort • • • Lupus anticoagulant Anti-cardiolipin Anti-B2 GP (LAC) (ACA) (ABA) prevalence 26% 47% 33% Any antiphospholipid antibody associated with arterial and venous thromboses, however • LAC (51%)> ACA or ABA (31%) • Only LAC is associated with myocardial infarction, OR 2.1 None of the antiphospholipid antibodies are associated with carotid plaques Petri, Lupus 2010 8 07-03-2011 Department of Rheumatology, Rigshospitalet Factors that may be associated with development of CVD in SLE • Standard risk factors • • • • • • • Disease related factors • • • • • • • • Age Hypertension Hyperlipidemia Hyperglycemia Smoking Obesity Systemic inflammation Autoantibodies Circulating immune complexes Activated complement products Nephritis Inflammation-associated lipid profile Inflammation-associated insulin resistance Hahn NEJM 2003 Adverse and protective effects of drugs • • • • Hydroxychloroquine (HCQ) Prednisolone Biologics NSAIDs Department of Rheumatology, Rigshospitalet Factors that may be associated with development of CVD in SLE • Standard risk factors • • • • • • • Disease related factors • • • • • • • • Age Hypertension Hyperlipidemia Hyperglycemia Smoking Obesity Systemic inflammation Autoantibodies Circulating immune complexes Activated complement products Nephritis Inflammation-associated lipid profile Inflammation-associated insulin resistance Hahn NEJM 2003 Adverse and protective effects of drugs • • • • Hydroxychloroquine (HCQ) Prednisolone Biologics NSAIDs 9 07-03-2011 Department of Rheumatology, Rigshospitalet Department of Rheumatology, Rigshospitalet 10 07-03-2011 Department of Rheumatology, Rigshospitalet Department of Rheumatology, Rigshospitalet Hydroxychloroquine as an anti-thrombotic • 1960-70ies HCQ, 600-1200 mg daily • ”desludging” agent • Prevention of deep venous thrombosis and pulmonary embolism • Hematological effects • • • • Red blod cell adhesion  Blood viscosity  Platelet aggregation  Immunological effects • • • Inhibition of TLR signalling Antigen processing and presentation  T-cell signaling  Petri, Curr Rheumatol Rep 2011 11 07-03-2011 Department of Rheumatology, Rigshospitalet Department of Rheumatology, Rigshospitalet - Lipids and inflammation combine to produce atherosclerosis - HDL may counteract this HDL HDL Oxidized LDL HDL Hahn et al, J Autoimmunity 2007 12 07-03-2011 Department of Rheumatology, Rigshospitalet - Lipids and inflammation combine to produce atherosclerosis - HDL may counteract this - but inflammatorically changed HDL HDL HDL Oxidized LDL HDL Hahn et al, J Autoimmunity 2007 13