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Coronary risk in autoimmune rheumatological diseases: an unfolding saga and perspective for Asian Indians
Indian Journal of Rheumatology 2008 December Volume 3, Number 4; pp. 137–138
Editorial
Coronary risk in autoimmune rheumatological diseases: an unfolding saga and perspective for Asian Indians A Misra
A decade ago, patients with SLE were dying relatively young, toll being taken by infections and renal failure. Many patients are surviving longer; a 10-year survival rate of patients with SLE has been reported to be ∼90%.1 Longer life course in patients with SLE has unveiled new problems; the dyslipidaemia, the metabolic syndrome and coronary heart disease (CHD). Recent data indicate that risk of myocardial infarction is seven-fold higher in all age groups and nearly 50-fold higher between 35 and 44 years in women with SLE as compared to age-matched women without SLE.2 Why do lupus patients have high cardiovascular risk? The following need consideration: accelerated atherosclerosis by conventionally defined pathways, contribution of autoimmunity to this process, a procoagulant tendency, and presence of vasculitis. Patients with autoimmune diseases thus provide unique opportunity to research multiple pathophysiological factors conventional and non-conventional, which may cause accelerated atherosclerosis.3 Undoubtedly, patients with SLE having conventional risk factors (smoking, obesity, type 2 diabetes, dyslipidemia, family history of premature CHD) are at a higher risk for CHD.4 Treatment with corticosteroids could worsen almost all conventional risk factors and has been independently reported to correlate with CHD.5 Dyslipidaemic profile correlating with glucocorticoid therapy has also been reported in the article in the current issue of the journal.5 Importantly, conventional risk factors could be affected by widespread activation of autoimmune mechanisms. Dyslipidaemia in SLE is characterized by hypertriglyceridemia, low levels of HDL cholesterol and high levels of oxidized LDL particles (‘lupus dysproteinemia’). Auto-antibodies to lipoprotein lipase impair its ability to hydrolyse circulating triglycerides, causing hypertriglyceridemia.6 Further, binding of autoantibodies to HDL/Apo A-1 leads to an increased clearance of HDL, resulting in low levels. These processes lead to lipid peroxidation and accelerated foam cell formation. It is also
interesting to note that HDL particles isolated from patients with SLE have impaired capacity to prevent LDL oxidation, and are ‘pro-inflammatory’.7 What is the relevance of this topic to Asian Indians? It is well known that Asian Indians have more abdominal adiposity, the metabolic syndrome, diabetes, dyslipidemia, than other ethnic groups.8–10 Indeed, India tops the list of countries with large number of patients with diabetes and CHD.11–13 Almost one-third of urban adults in India have the metabolic syndrome14,15 and these subjects frequently have ‘atherogenic dyslipidemia’ (high levels of triglycerides, low levels of HDL-C, and high levels of small-dense LDL), akin to ‘lupus dysproteinemia’. An Asian Indian is at a higher cardiovascular risk due to presence of these metabolic abnormalities even before onset of SLE. Autoimmune process in SLE also causes endothelial apoptosis and defective endothelial repair, resulting in loss of integrity of endothelium, prothrombotic milieu, and site for initiation of atherosclerosis.16 The most interesting possibility relating to aetiology of accelerated atherosclerosis is widespread inflammation, recognized by high levels of highsensitivity C-reactive protein (hs-CRP). Low-grade inflammation, typified by hs-CRP levels between 1 and 10 mg/dL, without presence of clinically manifest infection of inflammatory disease, is believed to be due to atherosclerosis, and predict future CHD.17 Interestingly, Asian Indians have higher levels of hs-CRP than white Caucasians.18 However, there are differences between hs-CRP levels between patients without autoimmune diseases (low levels, ‘sub-clinical inflammation’) and much higher levels seen in patients with autoimmune diseases. Is marked clinical inflammation in SLE and RA also directed towards endothelium of the arteries to accelerate atherosclerosis? The evidence suggests that this may be the case. The metabolic syndrome was reported to be directly correlated with high CRP levels but not with disease activity19 and CRP levels correlate with the presence
Department of Diabetes and Metabolic Diseases, Fortis Hospital, Vasant Kunj, New Delhi, India. Correspondence: Prof. Anoop Misra, email: [email protected]
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Indian Journal of Rheumatology 2008 December; Vol. 3, No. 4
of atherosclerosis in patients with SLE.20 However, hs-CRP may lose discriminatory power to predict CHD in the presence of chronic inflammatory diseases and chronic subclinical infections.3 One fact stands clear; suppressing disease activity in SLE has not translated into cardiovascular benefit. So what is the good news? We can apply evidence-based knowledge regarding aggressive prevention and management of CHD derived from other diseases (e.g. type 2 diabetes).21 For example, more aggressive use of HMG-CoA reductase inhibitors and aspirin has been proposed. Interestingly, both drugs have anti-inflammatory properties and reduce CRP levels. Use of balanced diets, physical activity and such drugs is probably more required for Asian Indians, with more than usual share of insulin resistance, the metabolic syndrome and CHD.
7.
8.
9.
10. 11.
ACKNOWLEDGEMENTS
12.
Source of funding: Nil. Disclosure statement: Author has declared no conflict of interest.
13.
REFERENCES 1.
2.
3.
4.
5.
6.
Borchers AT, Keen CL, Shoenfeld Y, Gershwin ME. Surviving the butterfly and the wolf: mortality trends in systemic lupus erythematosus. Autoimmun Rev 2004; 3: 423–53. Manzi S, Meilahn EN, Rairie JE, et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol 1997; 145: 408–15. Roman MJ, Shanker BA, Davis A, et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003; 349: 2399–406. Bultink IE, Turkstra F, Diamant M, Dijkmans BA, Voskuyl AE. Prevalence of and risk factors for the metabolic syndrome in women with systemic lupus erythematosus. Clin Exp Rheumatol 2008; 26: 32–8. Doria A, Shoenfeld Y, Wu R, et al. Risk factors for subclinical atherosclerosis in a prospective cohort of patients with systemic lupus erythematosus. Ann Rheum Dis 2003; 62: 1071–7. de Carvalho JF, Borba EF, Viana VS, Bueno C, Leon EP, Bonfa E. Anti-lipoprotein lipase antibodies: a new player in the complex atherosclerotic process in systemic lupus erythematosus? Arthritis Rheum 2004; 50: 3610–5.
14.
15. 16.
17.
18.
19.
20.
21.
Misra
McMahon M, Grossman J, FitzGerald J, et al. Proinflammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 2006; 54: 2541–9. Misra A, Wasir JS, Vikram NK. Carbohydrate diets, postprandial hyperlipidaemia, abdominal obesity and Asian Indians: a recipe for atherogenic disaster. Indian J Med Res 2005; 121: 5–8. Misra A, Vikram NK, Sharma R, Basit A. High prevalence of obesity and associated risk factors in urban children in India and Pakistan highlights immediate need to initiate primary prevention program for diabetes and coronary heart disease in schools. Diabetes Res Clin Pract 2006; 71: 101–2. Misra A, Ganda OP. Migration and its impact on adiposity and type 2 diabetes. Nutrition 2007; 23: 696–708. Gupta R, Misra A, Pais P, Rastogi P, Gupta VP. Correlation of regional cardiovascular disease mortality in India with lifestyle and nutritional factors. Int J Cardiol 2006; 108: 291–300. Misra A, Khurana L. Obesity and the metabolic syndrome in developing countries. J Clin Endocrinol Metab 2008 (in press). Gupta R, Misra A. Type 2 diabetes in India; regional disparities. Br J Diabetes Vascular Dis 2007; 7: 12–6. Misra A, Misra R, Wijesuriya M, Banerjee D. The metabolic syndrome in South Asians: continuing escalation and possible solutions. Indian J Med Res 2007; 125: 345–54. Misra A, Khurana L, Isharwal S, Bhardwaj S. South Asian diets and insulin resistance. Br J Nutr 2008; 9: 1–9. Rajagopalan S, Somers EC, Brook RD, et al. Endothelial cell apoptosis in systemic lupus erythematosus: a common pathway for abnormal vascular function and thrombosis propensity. Blood 2004; 103: 3677–83. Rifai N. C-reactive protein and coronary heart disease: diagnostic and therapeutic implications for primary prevention. Cardiovasc Toxicol 2001; 1: 153–7. Chambers JC, Eda S, Bassett P, et al. C-reactive protein, insulin resistance, central obesity, and coronary heart disease risk in Indian Asians from the United Kingdom compared with European whites. Circulation 2001; 104: 145–50. Chung CP, Avalos I, Oeser A, et al. High prevalence of the metabolic syndrome in patients with systemic lupus erythematosus: association with disease characteristics and cardiovascular risk factors. Ann Rheum Dis 2007; 66: 208–14. Svenungsson E, Fei GZ, Jensen-Urstad K, de Faire U, Hamsten A, Frostegard J. TNF-alpha: a link between hypertriglyceridaemia and inflammation in SLE patients with cardiovascular disease. Lupus 2003; 12: 454–61. Wajed J, Ahmad Y, Durrington PN, Bruce IN. Prevention of cardiovascular disease in systemic lupus erythematosus— proposed guidelines for risk factor management. Rheumatology (Oxford) 2004; 43: 7–12.
Editorial
Coronary risk in autoimmune rheumatological diseases: an unfolding saga and perspective for Asian Indians A Misra
A decade ago, patients with SLE were dying relatively young, toll being taken by infections and renal failure. Many patients are surviving longer; a 10-year survival rate of patients with SLE has been reported to be ∼90%.1 Longer life course in patients with SLE has unveiled new problems; the dyslipidaemia, the metabolic syndrome and coronary heart disease (CHD). Recent data indicate that risk of myocardial infarction is seven-fold higher in all age groups and nearly 50-fold higher between 35 and 44 years in women with SLE as compared to age-matched women without SLE.2 Why do lupus patients have high cardiovascular risk? The following need consideration: accelerated atherosclerosis by conventionally defined pathways, contribution of autoimmunity to this process, a procoagulant tendency, and presence of vasculitis. Patients with autoimmune diseases thus provide unique opportunity to research multiple pathophysiological factors conventional and non-conventional, which may cause accelerated atherosclerosis.3 Undoubtedly, patients with SLE having conventional risk factors (smoking, obesity, type 2 diabetes, dyslipidemia, family history of premature CHD) are at a higher risk for CHD.4 Treatment with corticosteroids could worsen almost all conventional risk factors and has been independently reported to correlate with CHD.5 Dyslipidaemic profile correlating with glucocorticoid therapy has also been reported in the article in the current issue of the journal.5 Importantly, conventional risk factors could be affected by widespread activation of autoimmune mechanisms. Dyslipidaemia in SLE is characterized by hypertriglyceridemia, low levels of HDL cholesterol and high levels of oxidized LDL particles (‘lupus dysproteinemia’). Auto-antibodies to lipoprotein lipase impair its ability to hydrolyse circulating triglycerides, causing hypertriglyceridemia.6 Further, binding of autoantibodies to HDL/Apo A-1 leads to an increased clearance of HDL, resulting in low levels. These processes lead to lipid peroxidation and accelerated foam cell formation. It is also
interesting to note that HDL particles isolated from patients with SLE have impaired capacity to prevent LDL oxidation, and are ‘pro-inflammatory’.7 What is the relevance of this topic to Asian Indians? It is well known that Asian Indians have more abdominal adiposity, the metabolic syndrome, diabetes, dyslipidemia, than other ethnic groups.8–10 Indeed, India tops the list of countries with large number of patients with diabetes and CHD.11–13 Almost one-third of urban adults in India have the metabolic syndrome14,15 and these subjects frequently have ‘atherogenic dyslipidemia’ (high levels of triglycerides, low levels of HDL-C, and high levels of small-dense LDL), akin to ‘lupus dysproteinemia’. An Asian Indian is at a higher cardiovascular risk due to presence of these metabolic abnormalities even before onset of SLE. Autoimmune process in SLE also causes endothelial apoptosis and defective endothelial repair, resulting in loss of integrity of endothelium, prothrombotic milieu, and site for initiation of atherosclerosis.16 The most interesting possibility relating to aetiology of accelerated atherosclerosis is widespread inflammation, recognized by high levels of highsensitivity C-reactive protein (hs-CRP). Low-grade inflammation, typified by hs-CRP levels between 1 and 10 mg/dL, without presence of clinically manifest infection of inflammatory disease, is believed to be due to atherosclerosis, and predict future CHD.17 Interestingly, Asian Indians have higher levels of hs-CRP than white Caucasians.18 However, there are differences between hs-CRP levels between patients without autoimmune diseases (low levels, ‘sub-clinical inflammation’) and much higher levels seen in patients with autoimmune diseases. Is marked clinical inflammation in SLE and RA also directed towards endothelium of the arteries to accelerate atherosclerosis? The evidence suggests that this may be the case. The metabolic syndrome was reported to be directly correlated with high CRP levels but not with disease activity19 and CRP levels correlate with the presence
Department of Diabetes and Metabolic Diseases, Fortis Hospital, Vasant Kunj, New Delhi, India. Correspondence: Prof. Anoop Misra, email: [email protected]
138
Indian Journal of Rheumatology 2008 December; Vol. 3, No. 4
of atherosclerosis in patients with SLE.20 However, hs-CRP may lose discriminatory power to predict CHD in the presence of chronic inflammatory diseases and chronic subclinical infections.3 One fact stands clear; suppressing disease activity in SLE has not translated into cardiovascular benefit. So what is the good news? We can apply evidence-based knowledge regarding aggressive prevention and management of CHD derived from other diseases (e.g. type 2 diabetes).21 For example, more aggressive use of HMG-CoA reductase inhibitors and aspirin has been proposed. Interestingly, both drugs have anti-inflammatory properties and reduce CRP levels. Use of balanced diets, physical activity and such drugs is probably more required for Asian Indians, with more than usual share of insulin resistance, the metabolic syndrome and CHD.
7.
8.
9.
10. 11.
ACKNOWLEDGEMENTS
12.
Source of funding: Nil. Disclosure statement: Author has declared no conflict of interest.
13.
REFERENCES 1.
2.
3.
4.
5.
6.
Borchers AT, Keen CL, Shoenfeld Y, Gershwin ME. Surviving the butterfly and the wolf: mortality trends in systemic lupus erythematosus. Autoimmun Rev 2004; 3: 423–53. Manzi S, Meilahn EN, Rairie JE, et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol 1997; 145: 408–15. Roman MJ, Shanker BA, Davis A, et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003; 349: 2399–406. Bultink IE, Turkstra F, Diamant M, Dijkmans BA, Voskuyl AE. Prevalence of and risk factors for the metabolic syndrome in women with systemic lupus erythematosus. Clin Exp Rheumatol 2008; 26: 32–8. Doria A, Shoenfeld Y, Wu R, et al. Risk factors for subclinical atherosclerosis in a prospective cohort of patients with systemic lupus erythematosus. Ann Rheum Dis 2003; 62: 1071–7. de Carvalho JF, Borba EF, Viana VS, Bueno C, Leon EP, Bonfa E. Anti-lipoprotein lipase antibodies: a new player in the complex atherosclerotic process in systemic lupus erythematosus? Arthritis Rheum 2004; 50: 3610–5.
14.
15. 16.
17.
18.
19.
20.
21.
Misra
McMahon M, Grossman J, FitzGerald J, et al. Proinflammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 2006; 54: 2541–9. Misra A, Wasir JS, Vikram NK. Carbohydrate diets, postprandial hyperlipidaemia, abdominal obesity and Asian Indians: a recipe for atherogenic disaster. Indian J Med Res 2005; 121: 5–8. Misra A, Vikram NK, Sharma R, Basit A. High prevalence of obesity and associated risk factors in urban children in India and Pakistan highlights immediate need to initiate primary prevention program for diabetes and coronary heart disease in schools. Diabetes Res Clin Pract 2006; 71: 101–2. Misra A, Ganda OP. Migration and its impact on adiposity and type 2 diabetes. Nutrition 2007; 23: 696–708. Gupta R, Misra A, Pais P, Rastogi P, Gupta VP. Correlation of regional cardiovascular disease mortality in India with lifestyle and nutritional factors. Int J Cardiol 2006; 108: 291–300. Misra A, Khurana L. Obesity and the metabolic syndrome in developing countries. J Clin Endocrinol Metab 2008 (in press). Gupta R, Misra A. Type 2 diabetes in India; regional disparities. Br J Diabetes Vascular Dis 2007; 7: 12–6. Misra A, Misra R, Wijesuriya M, Banerjee D. The metabolic syndrome in South Asians: continuing escalation and possible solutions. Indian J Med Res 2007; 125: 345–54. Misra A, Khurana L, Isharwal S, Bhardwaj S. South Asian diets and insulin resistance. Br J Nutr 2008; 9: 1–9. Rajagopalan S, Somers EC, Brook RD, et al. Endothelial cell apoptosis in systemic lupus erythematosus: a common pathway for abnormal vascular function and thrombosis propensity. Blood 2004; 103: 3677–83. Rifai N. C-reactive protein and coronary heart disease: diagnostic and therapeutic implications for primary prevention. Cardiovasc Toxicol 2001; 1: 153–7. Chambers JC, Eda S, Bassett P, et al. C-reactive protein, insulin resistance, central obesity, and coronary heart disease risk in Indian Asians from the United Kingdom compared with European whites. Circulation 2001; 104: 145–50. Chung CP, Avalos I, Oeser A, et al. High prevalence of the metabolic syndrome in patients with systemic lupus erythematosus: association with disease characteristics and cardiovascular risk factors. Ann Rheum Dis 2007; 66: 208–14. Svenungsson E, Fei GZ, Jensen-Urstad K, de Faire U, Hamsten A, Frostegard J. TNF-alpha: a link between hypertriglyceridaemia and inflammation in SLE patients with cardiovascular disease. Lupus 2003; 12: 454–61. Wajed J, Ahmad Y, Durrington PN, Bruce IN. Prevention of cardiovascular disease in systemic lupus erythematosus— proposed guidelines for risk factor management. Rheumatology (Oxford) 2004; 43: 7–12.