研究背景:
冠狀動脈心臟疾病與腦血管疾病中風是國人十大死因前幾名，常導致患者殘廢或死亡，對健康造成很大的威脅，此兩種疾病皆由動脈粥狀硬化所致，近年來對動脈粥狀硬化的致病機轉研究發現，發炎時的免疫反應會促使動脈硬化的進展及生成。全身自體免疫疾病臨床表現各異，但多處於慢性發炎狀態；之前的研究即發現類風濕性關節炎與全身性紅斑狼瘡病人會增加冠狀動脈心臟病與腦血管疾病的併發，卻無法以傳統心血管危險因子來解釋，這結果暗示慢性發炎扮演著重要的角色。然而，其他處於慢性發炎的自體免疫風濕疾病是否也會增加此危險，目前並不清楚。

研究目的:
基於粥狀動脈硬化是慢性發炎疾病的理論，本研究的假說為: 自體免疫風濕疾病皆會增加冠狀動脈心臟病與中風的危險。研究目的即在證實包括:類風濕性關節炎、全身性紅斑狼瘡、乾燥症、硬皮症、貝西氏症、皮肌炎、多發性肌炎和血管炎等自體免疫疾病皆會增加冠狀動脈心臟疾病及中風的風險。

研究方法:
全身自體免疫疾病多屬重大傷病，本研究方法以2000至2010年，全民健保資料庫中的重大傷病檔案，診斷類風濕性關節炎、全身性紅斑狼瘡、乾燥症、硬皮症、貝西氏症、皮肌炎、多發性肌炎和血管炎者，年齡大於18歲的病人作為硏究組，所有的病人從重大傷病卡核發開始追蹤到冠狀動脈心臟疾病、中風發生，死亡、或是至2010年底。控制組則以2000年百萬歸人檔與硏究組匹配年齡、性別、診斷期間；高血壓、高血脂、糖尿病等傳統危險因子以及相關藥物後，統計分析冠狀動脈心臟疾病與中風於各風濕疾病族群發生率，再比較其冠狀動脈心臟疾病和中風的危險性，以證明自體免疫風濕疾病本身即具有冠狀動脈心臟病與中風的風險。

研究結果:
在2003至2010年硏究期間，自體免疫風濕疾病病人總共有41,994位，對照組為732,723位，冠狀動脈心臟病平均追踪時間是3.6年，中風則是3.8年，在校正各風險因素後和對照組相較，類風濕性關節炎發生冠狀動脈心臟病的風險大約是對照組的5倍，乾燥症6倍、全身性紅斑狼瘡4倍、硬皮症4倍、貝西氏症5倍、皮肌炎2倍、多發性肌炎4倍和血管炎者4倍。另外，類風濕性關節炎發生中風的風險約是對照組的2倍，乾燥症3倍、全身性紅斑狼瘡4倍、硬皮症2倍、貝西氏症5倍、皮肌炎2倍、多發性肌炎2倍和血管炎者3倍。

研究結論:
硏究結果證實，於本硏究中的所有自體免疫風濕疾病皆有較高冠狀動脈心臟病和中風的風險。此結果可提供相關臨床照護者提高對於此問題的重視，並且提早做出預防措施，以降低冠狀動脈心臟疾病與中風相關的罹病率以及死亡率，其中詳細的致病機轉尚需後續的研究來闡明。

Background:
Coronary heart disease (CHD) and ischemic stroke (IS) is a major health problem in developed countries, for which are potentially lethal complications. It is increasingly understand that Inflammation significantly linked to CHD and IS that the innate and adaptive immune systems play an important role in the initiation and progression of arthrosclerosis. Autoimmune rheumatic diseases (ARD) are a group of diseases characterized by chronic multisystem inflammation with various clinical presentations. The inflammation associated with ARD increased beyond what is explained by traditional CHD risk factors suggested that ARD may be at increased risk for CHD and IS. Previous studies have indicated that RA and SLE were associated with increased risk of CHD and IS. However, these studies have often been small and done mostly in individual ARD and did not control for major cardiovascular risk factors.

Objectives:
The objective of our study was to determine if ARD including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren’s syndrome (SjS), Scleroderma, Behcet’s disease, dermatomyositis, polymyositis and systemic vasculitis itself is the risk factor of CHD and IS based on inflammation theory of atherosclerosis using population-based cohort study.

Methods:
The catatrophic illness files of the NHIRD was used to establish the cohort of ARD in the study. The comparison group was from the Longitudinal Health Insurance Database 2000 (LHID 2000). The International Classification of Disease, Ninth Revision (ICD-9) was used for coding the diagnosis of disease. A retrospective, population-based cohort in Taiwan of patients with ARD included RA, SLE, primary Sjogren’s syndrome, Scleroderma, Behcet’s disease, dermatomyositis, polymyositis and vasculitis were confined to those aged ≧18 years between 2000 and 2010, comparing outcomes among patients without a diagnosis of ARD. The control subjects for ARD cases were time matched, randomly selected then adjusted for age, gender, traditional risks of atherosclerosis and related medications. Cox proportional hazards regression models were used to calculate the hazard ratio of CHD and ischemic stroke for individual ARD compared with the control group. The Kaplan–Meier method was used to compare the cumulative incidences of CHD and ischemic stroke in patients with and without ARD. A p-value of <0.05 was considered significant. Additionally, we performed propensity score method with 5-to-1 greedy matching technique to create more homogenous groups for comparisons.

Results:
A total of 41994 patients with ARD and 732,723 control patients aged ≧18 years were identified between 2003 and 2010. There were 20898 patients with RA, 9885 with primary Sjogren’ s syndrome, 7710 with systemic lupus erythematosus (SLE), 1023 of systemic sclerosis, 988 with Behcet’s disease, 640 of dermatomyositis, 505 of polymyositis and 414 patients with vasculitis in our study. The mean follow-up time was 3.6 years for CHD and 3.8 years for IS. The peak incidence of RA, Sjogren’ syndrome, scleroderma, dermatomyositis and polymyositis was at age of 51-65 years. The peak incident of SLE was age of 18-35 years and 36-50 years for Behcet’s disease. The three most common ARD in Taiwan were RA, Sjogren’s syndrome and SLE.
The incidence rate of CHD and IS was higher in the ARD patients than in the comparison group. Autoimmune rheumatic diseases including RA, Sjogren’s syndrome, SLE, scleroderma, Behcet’s disease, dermatomyositis, polymyositis and vasculitis were all associated with increased risk of CHD and IS. Relative to the comparison cohorts, the adjusted HRs for coronary heart disease were 5.22 (95% CI 4.97 to 5.49) for RA, 6.11 (95% CI 5.75 to 6.51) for Sjogren’s syndrome, 4.02 for SLE (95% CI 3.63 to 4.46), 3.94 for scleroderma (95% CI 3.30 to 4.71), 5.34 for BD (95% CI 4.02 to 7.10), 2.21 for dermatomyositis (95% CI 1.64 to 2.99), 3.73 (95% CI 2.83 to 4.90) for polymyositis and 4.34 (95% CI 3.31 to 5.68) for vasculitis. The adjusted HRs for ischemic stroke were 2.43 (95% CI 2.25 to 2.63) for RA, 3.17 (95% CI 2.87 to 3.50) for Sjogren’s syndrome, 3.63 for SLE (95% CI 3.14 to 4.19), 2.13 for scleroderma (95% CI 1.56 to 2.92), 4.77 for BD (95% CI 3.10 to 7.33), 2.01 for dermatomyositis (95% CI 1.36 to 3.20), 1.99 (95% CI 1.25 to 3.17) for polymyositis and 2.75 (95% CI 1.75 to 4.32) for vasculitis.

Conclusion:
The results of this general population-based study suggest that all ARDs are associated with an increased risk of coronary heart disease and ischemic stroke. Our findings will support efforts to improve CHD and IS prevention and monitoring among ARDs patients, as CHD and IS risk modification represents an opportunity to further reduce the morbidity and mortality of ARD. Further studies are needed to elucidate the exact mechanisms of CHD and IS in ARD patients.

1. Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization. Circulation. 2001 Nov 27; 104(22):2746-2753.
2. Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular diseases: Part II: variations in cardiovascular disease by specific ethnic groups and geographic regions and prevention strategies. Circulation. 2001 Dec 4; 104(23):2855-2864.
3. Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, et al. Executive summary: heart disease and stroke statistics--2010 update: a report from the American Heart Association. Circulation. 2010 Feb 23; 121(7):948-954.
4. Weyand CM, Goronzy JJ, Liuzzo G, Kopecky SL, Holmes DR, Jr., Frye RL. T-cell immunity in acute coronary syndromes. Mayo Clin Proc. 2001 Oct; 76(10):1011-1020.
5. Liuzzo G, Goronzy JJ, Yang H, Kopecky SL, Holmes DR, Frye RL, et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation. 2000 Jun 27; 101(25):2883-2888.
6. Niessner A, Sato K, Chaikof EL, Colmegna I, Goronzy JJ, Weyand CM. Pathogen-sensing plasmacytoid dendritic cells stimulate cytotoxic T-cell function in the atherosclerotic plaque through interferon-alpha. Circulation. 2006 Dec 5; 114(23):2482-2489.
7. Gonzalez-Gay MA, Gonzalez-Juanatey C, Martin J. Rheumatoid arthritis: a disease associated with accelerated atherogenesis. Semin Arthritis Rheum. 2005 Aug; 35(1):8-17.
8. Solomon DH, Karlson EW, Rimm EB, Cannuscio CC, Mandl LA, Manson JE, et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation. 2003 Mar 11; 107(9):1303-1307.
9. Hak AE, Karlson EW, Feskanich D, Stampfer MJ, Costenbader KH. Systemic lupus erythematosus and the risk of cardiovascular disease: results from the nurses' health study. Arthritis Rheum. 2009 Oct 15; 61(10):1396-1402.
10. Ngian GS, Sahhar J, Proudman SM, Stevens W, Wicks IP, Van Doornum S. Prevalence of coronary heart disease and cardiovascular risk factors in a national cross-sectional cohort study of systemic sclerosis. Ann Rheum Dis. 2012 Dec; 71(12):1980-1983.
11. Wu XF, Huang JY, Chiou JY, Chen HH, Wei JC, Dong LL. Increased risk of coronary heart disease among patients with primary Sjogren's syndrome: a nationwide population-based cohort study. Sci Rep. 2018 Feb 2; 8(1):2209.
12. Gabriel SE, Crowson CS, Kremers HM, Doran MF, Turesson C, O'Fallon WM, et al. Survival in rheumatoid arthritis: a population-based analysis of trends over 40 years. Arthritis Rheum. 2003 Jan; 48(1):54-58.
13. del Rincon ID, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum. 2001 Dec; 44(12):2737-2745.
14. Gonzalez A, Maradit Kremers H, Crowson CS, Ballman KV, Roger VL, Jacobsen SJ, et al. Do cardiovascular risk factors confer the same risk for cardiovascular outcomes in rheumatoid arthritis patients as in non-rheumatoid arthritis patients? Ann Rheum Dis. 2008 Jan; 67(1):64-69.
15. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005 Apr 21; 352(16):1685-1695.
16. Sherer Y, Shoenfeld Y. Mechanisms of disease: atherosclerosis in autoimmune diseases. Nat Clin Pract Rheumatol. 2006 Feb; 2(2):99-106.
17. El-Magadmi M, Bodill H, Ahmad Y, Durrington PN, Mackness M, Walker M, et al. Systemic lupus erythematosus: an independent risk factor for endothelial dysfunction in women. Circulation. 2004 Jul 27; 110(4):399-404.
18. Bruce IN, Urowitz MB, Gladman DD, Ibanez D, Steiner G. Risk factors for coronary heart disease in women with systemic lupus erythematosus: the Toronto Risk Factor Study. Arthritis Rheum. 2003 Nov; 48(11):3159-3167.
19. Dalakas MC, Hohlfeld R. Polymyositis and dermatomyositis. Lancet. 2003 Sep 20; 362(9388):971-982.
20. Plotz PH, Dalakas M, Leff RL, Love LA, Miller FW, Cronin ME. Current concepts in the idiopathic inflammatory myopathies: polymyositis, dermatomyositis, and related disorders. Ann Intern Med. 1989 Jul 15; 111(2):143-157.
21. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975 Feb 13; 292(7):344-347.
22. Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med. 1975 Feb 20; 292(8):403-407.
23. Amato AA, Barohn RJ. Evaluation and treatment of inflammatory myopathies. J Neurol Neurosurg Psychiatry. 2009 Oct; 80(10):1060-1068.
24. See LC, Kuo CF, Chou IJ, Chiou MJ, Yu KH. Sex- and age-specific incidence of autoimmune rheumatic diseases in the Chinese population: a Taiwan population-based study. Semin Arthritis Rheum. 2013 Dec; 43(3):381-386.
25. Bernatsky S, Joseph L, Pineau CA, Belisle P, Boivin JF, Banerjee D, et al. Estimating the prevalence of polymyositis and dermatomyositis from administrative data: age, sex and regional differences. Ann Rheum Dis. 2009 Jul; 68(7):1192-1196.
26. Danko K, Ponyi A, Constantin T, Borgulya G, Szegedi G. Long-term survival of patients with idiopathic inflammatory myopathies according to clinical features: a longitudinal study of 162 cases. Medicine (Baltimore). 2004 Jan; 83(1):35-42.
27. Airio A, Kautiainen H, Hakala M. Prognosis and mortality of polymyositis and dermatomyositis patients. Clin Rheumatol. 2006 Mar; 25(2):234-239.
28. Dobloug GC, Svensson J, Lundberg IE, Holmqvist M. Mortality in idiopathic inflammatory myopathy: results from a Swedish nationwide population-based cohort study. Ann Rheum Dis. 2018 Jan; 77(1):40-47.
29. Nussinovitch U, Shoenfeld Y. Intravenous immunoglobulin - indications and mechanisms in cardiovascular diseases. Autoimmun Rev. 2008 Jun; 7(6):445-452.
30. Hansson GK. Inflammation and Atherosclerosis: The End of a Controversy. Circulation. 2017 Nov 14; 136(20):1875-1877.
31. Ford ES, Giles WH. Serum C-reactive protein and fibrinogen concentrations and self-reported angina pectoris and myocardial infarction: findings from National Health and Nutrition Examination Survey III. J Clin Epidemiol. 2000 Jan; 53(1):95-102.
32. Crea F, Liuzzo G. Pathogenesis of acute coronary syndromes. J Am Coll Cardiol. 2013 Jan 8; 61(1):1-11.
33. Falk E, Nakano M, Bentzon JF, Finn AV, Virmani R. Update on acute coronary syndromes: the pathologists' view. Eur Heart J. 2013 Mar; 34(10):719-728.
34. Kao AH, Wasko MC, Krishnaswami S, Wagner J, Edmundowicz D, Shaw P, et al. C-reactive protein and coronary artery calcium in asymptomatic women with systemic lupus erythematosus or rheumatoid arthritis. Am J Cardiol. 2008 Sep 15; 102(6):755-760.
35. National Health Insurance Administration, Ministry of Health and Welfare, Taiwan, R.O.C. (2014). National Health Insurance Annual Report 2014-2015.
36. https://www.nhi.gov.tw/english/Content_List.aspx?n=F5B8E49CB4548C60&topn=1D1ECC54F86E9050.
37. https://nhird.nhri.org.tw/en/Data_Subsets.html.
38. Cheng CL, Lee CH, Chen PS, Li YH, Lin SJ, Yang YH. Validation of acute myocardial infarction cases in the national health insurance research database in taiwan. J Epidemiol. 2014; 24(6):500-507.
39. Sultan SM, Ioannou Y, Moss K, Isenberg DA. Outcome in patients with idiopathic inflammatory myositis: morbidity and mortality. Rheumatology (Oxford). 2002 Jan; 41(1):22-26.
40. Hochberg MC, Feldman D, Stevens MB. Adult onset polymyositis/dermatomyositis: an analysis of clinical and laboratory features and survival in 76 patients with a review of the literature. Semin Arthritis Rheum. 1986 Feb; 15(3):168-178.
41. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet. 2006 May 27; 367(9524):1747-1757.
42. O'Hanlon TP, Carrick DM, Targoff IN, Arnett FC, Reveille JD, Carrington M, et al. Immunogenetic risk and protective factors for the idiopathic inflammatory myopathies: distinct HLA-A, -B, -Cw, -DRB1, and -DQA1 allelic profiles distinguish European American patients with different myositis autoantibodies. Medicine (Baltimore). 2006 Mar; 85(2):111-127.
43. Holmqvist ME, Wedren S, Jacobsson LT, Klareskog L, Nyberg F, Rantapaa-Dahlqvist S, et al. Rapid increase in myocardial infarction risk following diagnosis of rheumatoid arthritis amongst patients diagnosed between 1995 and 2006. J Intern Med. 2010 Dec; 268(6):578-585.
44. Sattar N, McInnes IB. Vascular comorbidity in rheumatoid arthritis: potential mechanisms and solutions. Curr Opin Rheumatol. 2005 May; 17(3):286-292.
45. Sattar N, McCarey DW, Capell H, McInnes IB. Explaining how "high-grade" systemic inflammation accelerates vascular risk in rheumatoid arthritis. Circulation. 2003 Dec 16; 108(24):2957-2963.
46. Zoller B, Li X, Sundquist J, Sundquist K. Risk of subsequent coronary heart disease in patients hospitalized for immune-mediated diseases: a nationwide follow-up study from Sweden. PLoS One. 2012; 7(3):e33442.
47. Tisseverasinghe A, Bernatsky S, Pineau CA. Arterial events in persons with dermatomyositis and polymyositis. J Rheumatol. 2009 Sep; 36(9):1943-1946.
48. Lundberg IE. The heart in dermatomyositis and polymyositis. Rheumatology (Oxford). 2006 Oct; 45 Suppl 4:iv18-21.
49. Solomon DH, Kremer J, Curtis JR, Hochberg MC, Reed G, Tsao P, et al. Explaining the cardiovascular risk associated with rheumatoid arthritis: traditional risk factors versus markers of rheumatoid arthritis severity. Ann Rheum Dis. 2010 Nov; 69(11):1920-1925.
50. Brady SR, de Courten B, Reid CM, Cicuttini FM, de Courten MP, Liew D. The role of traditional cardiovascular risk factors among patients with rheumatoid arthritis. J Rheumatol. 2009 Jan; 36(1):34-40.
51. Esdaile JM, Abrahamowicz M, Grodzicky T, Li Y, Panaritis C, du Berger R, et al. Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus. Arthritis Rheum. 2001 Oct; 44(10):2331-2337.
52. Van Doornum S, McColl G, Wicks IP. Accelerated atherosclerosis: an extraarticular feature of rheumatoid arthritis? Arthritis Rheum. 2002 Apr; 46(4):862-873.
53. Asanuma Y, Oeser A, Shintani AK, Turner E, Olsen N, Fazio S, et al. Premature coronary-artery atherosclerosis in systemic lupus erythematosus. N Engl J Med. 2003 Dec 18; 349(25):2407-2415.
54. Weng MY, Lai EC, Kao Yang YH. Increased risk of coronary heart disease among patients with idiopathic inflammatory myositis: a nationwide population study in Taiwan. Rheumatology (Oxford). 2019 Mar 21.
55. Skaggs BJ, Hahn BH, McMahon M. Accelerated atherosclerosis in patients with SLE--mechanisms and management. Nat Rev Rheumatol. 2012 Feb 14; 8(4):214-223.
56. Wierzbicki AS. Lipids, cardiovascular disease and atherosclerosis in systemic lupus erythematosus. Lupus. 2000; 9(3):194-201.
57. Bruce IN, Gladman DD, Urowitz MB. Premature atherosclerosis in systemic lupus erythematosus. Rheum Dis Clin North Am. 2000 May; 26(2):257-278.
58. Behrouz R. The risk of ischemic stroke in major rheumatic disorders. J Neuroimmunol. 2014 Dec 15; 277(1-2):1-5.
59. Lindhardsen J, Ahlehoff O, Gislason GH, Madsen OR, Olesen JB, Svendsen JH, et al. Risk of atrial fibrillation and stroke in rheumatoid arthritis: Danish nationwide cohort study. Bmj. 2012 Mar 8; 344:e1257.
60. Bacani AK, Gabriel SE, Crowson CS, Heit JA, Matteson EL. Noncardiac vascular disease in rheumatoid arthritis: increase in venous thromboembolic events? Arthritis Rheum. 2012 Jan; 64(1):53-61.
61. Timlin H, Petri M. Transient ischemic attack and stroke in systemic lupus erythematosus. Lupus. 2013 Oct; 22(12):1251-1258.
62. Krishnan E. Stroke subtypes among young patients with systemic lupus erythematosus. Am J Med. 2005 Dec; 118(12):1415.
63. Man A, Zhu Y, Zhang Y, Dubreuil M, Rho YH, Peloquin C, et al. The risk of cardiovascular disease in systemic sclerosis: a population-based cohort study. Ann Rheum Dis. 2013 Jul; 72(7):1188-1193.
64. Cheng CL, Kao YH, Lin SJ, Lee CH, Lai ML. Validation of the National Health Insurance Research Database with ischemic stroke cases in Taiwan. Pharmacoepidemiol Drug Saf. 2011 Mar; 20(3):236-242.
65. Hu HH, Sheng WY, Chu FL, Lan CF, Chiang BN. Incidence of stroke in Taiwan. Stroke. 1992 Sep; 23(9):1237-1241.
66. Avina-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum. 2008 Dec 15; 59(12):1690-1697.
67. Sodergren A, Stegmayr B, Ohman ML, Wallberg-Jonsson S. Increased incidence of stroke and impaired prognosis after stroke among patients with seropositive rheumatoid arthritis. Clin Exp Rheumatol. 2009 Jul-Aug; 27(4):641-644.
68. Zoller B, Li X, Sundquist J, Sundquist K. Risk of subsequent ischemic and hemorrhagic stroke in patients hospitalized for immune-mediated diseases: a nationwide follow-up study from Sweden. BMC Neurol. 2012 Jun 18; 12:41.
69. Lindhardsen J, Ahlehoff O, Gislason GH, Madsen OR, Olesen JB, Torp-Pedersen C, et al. The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: a Danish nationwide cohort study. Ann Rheum Dis. 2011 Jun; 70(6):929-934.
70. Ungprasert P, Sanguankeo A, Upala S. Risk of ischemic stroke in patients with systemic sclerosis: A systematic review and meta-analysis. Mod Rheumatol. 2016; 26(1):128-131.
71. Ungprasert P, Cheungpasitporn W, Wijarnpreecha K, Ahuja W, Ratanasrimetha P, Thongprayoon C. Risk of ischemic stroke in patients with polymyositis and dermatomyositis: a systematic review and meta-analysis. Rheumatol Int. 2015 May; 35(5):905-909.
72. Mikdashi J, Handwerger B, Langenberg P, Miller M, Kittner S. Baseline disease activity, hyperlipidemia, and hypertension are predictive factors for ischemic stroke and stroke severity in systemic lupus erythematosus. Stroke. 2007 Feb; 38(2):281-285.