Lupus as a risk factor for cardiovascular disease SØREN JACOBSEN Department Rheumatology, Rigshospitalet Søren Jacobsen Main sponsors: Gigtforeningen Novo Nordisk Fonden Rigshospitalet Disclaimer: Novo Nordisk A/S Active Biotech AB GlaxoSmithKline Pharma Roche 1
Increased mortality in SLE Standardized mortality ratios in major clinical studies of SLE SLICC cohort, 1970-2001 2.4 (95% CI 2.3-2.5) Denmark, 1975-95 4.6 (95% CI 3.8-5.5) Canada 1970-77 10.1 1978-85 4.8 1986-94 3.3 Lupus nephritis, 1975-2007 6.8 (95% CI 4.9-9.4) 1971 79 9.0 (4.7 17.1) 1980 89 6.2 (4.0 9.5) 1990 95 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
The bimodal mortality pattern of SLE Urowitz et al. Am J Med 1976 CVD is among the leading causes of death in SLE Bernatsky et al, A&R 2006 9,547 patients 1255 deaths CVD 313 (25%) SMR: 1.7 (1.5 1.9) 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%) 3
Increased CVD mortality in SLE due to Increased cardiovascular morbidity (Manzi Am J Epid 1997) Increased case fatality Stroke No Myocardial infarction? Factors that may be associated with development of CVD in SLE Standard risk factors Age Hypertension Hyperlipidemia Hyperglycemia Smoking Obesity Disease related factors 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
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) Atherosclerosis - intermediate stage Increased Intima-media thickness Arterial stiffness Pulse wave velocity 5
Atherosclerosis - plaques Increased coronary artery calcifications on CT plaque formation on ultrasound Atherosclerosis - advanced plaques Vulnerable Ulcerated Ruptured 6
CASE Female patient with SLE Age 42: Arthralgias, Raynaud and photosensitivity Age 43: 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 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
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? Anti-phospholipid antibodies and CVD The Hopkins Lupus Cohort Lupus anticoagulant (LAC) 26% Anti-cardiolipin (ACA) 47% Anti-B2 GP (ABA) 33% prevalence 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
Factors that may be associated with development of CVD in SLE Standard risk factors Age Hypertension Hyperlipidemia Hyperglycemia Smoking Obesity Disease related factors 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 Factors that may be associated with development of CVD in SLE Standard risk factors Age Hypertension Hyperlipidemia Hyperglycemia Smoking Obesity Disease related factors 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
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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
- Lipids and inflammation combine to produce atherosclerosis - HDL may counteract this HDL Oxidized LDL HDL HDL Hahn et al, J Autoimmunity 2007 12
- Lipids and inflammation combine to produce atherosclerosis - HDL may counteract this - but inflammatorically changed HDL HDL Oxidized LDL HDL HDL Hahn et al, J Autoimmunity 2007 13