Original Research15 September 2015
A Population-Based Study
    Author, Article and Disclosure Information

    Ankylosing spondylitis (AS) is a chronic inflammatory arthritis affecting the spine in young adults. It is associated with excess cardiovascular and cerebrovascular morbidity.


    To determine whether patients with AS are at increased risk for cardiovascular and cerebrovascular mortality.


    Population-based retrospective cohort study using administrative health data.


    Ontario, Canada.


    21 473 patients with AS aged 15 years or older and 86 606 comparators without AS, matched for age, sex, and location of residence.


    The primary outcome was a composite of cardiovascular and cerebrovascular death. Hazard ratios (HRs) for vascular death were calculated; adjusted for history of cancer, diabetes, dementia, inflammatory bowel disease, hypertension, chronic kidney disease, and peripheral vascular disease; and, among those aged 66 years or older, relevant drug therapies. Independent risk factors for vascular mortality were identified in patients with AS.


    The mean age of patients with AS was 46 years, and 53% were male. Patients and comparators were followed for 166 920 and 686 461 patient-years, respectively. Adjusted HRs for vascular death in AS were 1.36 (95% CI, 1.13 to 1.65) overall, 1.46 (CI, 1.13 to 1.87) in men, and 1.24 (CI, 0.92 to 1.67) in women. Significant risk factors for vascular death were age; male sex; lower income; dementia; chronic kidney disease; peripheral vascular disease; and, among patients aged 65 years or older, lack of exposure to nonsteroidal anti-inflammatory drugs and statins.


    Diagnosis codes for AS were not validated in Ontario.


    Ankylosing spondylitis is associated with increased risk for vascular mortality. A comprehensive strategy to screen and treat modifiable vascular risk factors in AS is needed.

    Primary Funding Source:

    The Arthritis Program, University Health Network, Toronto; and The Arthritis Society, Canada.


    • 1. Azevedo VF Pecoits-Filho R Atherosclerosis and endothelial dysfunction in patients with ankylosing spondylitis. Rheumatol Int2010;30:1411-6. [PMID: 20349072] doi:10.1007/s00296-010-1416-3 CrossrefMedlineGoogle Scholar
    • 2. Vallance P Collier J Bhagat K Infection, inflammation, and infarction: does acute endothelial dysfunction provide a link? Lancet1997;349:1391-2. [PMID: 9149715] CrossrefMedlineGoogle Scholar
    • 3. Boring L Gosling J Cleary M Charo IF Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature1998;394:894-7. [PMID: 9732872] CrossrefMedlineGoogle Scholar
    • 4. Gu L Okada Y Clinton SK Gerard C Sukhova GK Libby P et alAbsence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell1998;2:275-81. [PMID: 9734366] CrossrefMedlineGoogle Scholar
    • 5. Bodnár N Kerekes G Seres I Paragh G Kappelmayer J Némethné ZG et alAssessment of subclinical vascular disease associated with ankylosing spondylitis. J Rheumatol2011;38:723-9. [PMID: 21239756] doi:10.3899/jrheum.100668 CrossrefMedlineGoogle Scholar
    • 6. Mathieu S Joly H Baron G Tournadre A Dubost JJ Ristori JM et alTrend towards increased arterial stiffness or intima-media thickness in ankylosing spondylitis patients without clinically evident cardiovascular disease. Rheumatology (Oxford)2008;47:1203-7. [PMID: 18524805] doi:10.1093/rheumatology/ken198 CrossrefMedlineGoogle Scholar
    • 7. Papagoras C Voulgari PV Drosos AA Atherosclerosis and cardiovascular disease in the spondyloarthritides, particularly ankylosing spondylitis and psoriatic arthritis. Clin Exp Rheumatol2013;31:612-20. [PMID: 23406817] MedlineGoogle Scholar
    • 8. Peters MJ vanEijk IC Smulders YM Serne E Dijkmans BA van der Horst-Bruinsma IE et alSigns of accelerated preclinical atherosclerosis in patients with ankylosing spondylitis. J Rheumatol2010;37:161-6. [PMID: 19955053] doi:10.3899/jrheum.090667 CrossrefMedlineGoogle Scholar
    • 9. Sari I Okan T Akar S Cece H Altay C Secil M et alImpaired endothelial function in patients with ankylosing spondylitis. Rheumatology (Oxford)2006;45:283-6. [PMID: 16204374] CrossrefMedlineGoogle Scholar
    • 10. van Eijk IC Peters MJ Serné EH van der Horst-Bruinsma IE Dijkmans BA Smulders YM et alMicrovascular function is impaired in ankylosing spondylitis and improves after tumour necrosis factor alpha blockade. Ann Rheum Dis2009;68:362-6. [PMID: 18390569] doi:10.1136/ard.2007.086777 CrossrefMedlineGoogle Scholar
    • 11. Szabo SM Levy AR Rao SR Kirbach SE Lacaille D Cifaldi M et alIncreased risk of cardiovascular and cerebrovascular diseases in individuals with ankylosing spondylitis: a population-based study. Arthritis Rheum2011;63:3294-304. [PMID: 21834064] doi:10.1002/art.30581 CrossrefMedlineGoogle Scholar
    • 12. Vinsonneau U Brondex A Mansourati J Saraux A Cornily JC Arlès F et alCardiovascular disease in patients with spondyloarthropathies. Joint Bone Spine2008;75:18-21. [PMID: 17913549] CrossrefMedlineGoogle Scholar
    • 13. Lautermann D Braun J Ankylosing spondylitis—cardiac manifestations. Clin Exp Rheumatol2002;20:S11-5. [PMID: 12463440] MedlineGoogle Scholar
    • 14. Dik VK Peters MJ Dijkmans PA Van der Weijden MA DeVries MK Dijkmans BA et alThe relationship between disease-related characteristics and conduction disturbances in ankylosing spondylitis. Scand J Rheumatol2010;39:38-41. [PMID: 20132069] doi:10.3109/03009740903096101 CrossrefMedlineGoogle Scholar
    • 15. Peters MJ Visman I Nielen MM VanDillen N Verheij RA van der Horst-Bruinsma IE et alAnkylosing spondylitis: a risk factor for myocardial infarction? Ann Rheum Dis2010;69:579-81. [PMID: 19403516] doi:10.1136/ard.2009.110593 CrossrefMedlineGoogle Scholar
    • 16. Huang YP Wang YH Pan SL Increased risk of ischemic heart disease in young patients with newly diagnosed ankylosing spondylitis—a population-based longitudinal follow-up study. PLoS One2013;8:e64155. [PMID: 23691161] doi:10.1371/journal.pone.0064155 CrossrefMedlineGoogle Scholar
    • 17. Hollan I Saatvedt K Almdahl SM Mikkelsen K Moer R Halvorsen P et alSpondyloarthritis: a strong predictor of early coronary artery bypass grafting. Scand J Rheumatol2008;37:18-22. [PMID: 18189190] doi:10.1080/03009740701716868 CrossrefMedlineGoogle Scholar
    • 18. Brophy S Cooksey R Atkinson M Zhou SM Husain MJ Macey S et alNo increased rate of acute myocardial infarction or stroke among patients with ankylosing spondylitis-a retrospective cohort study using routine data. Semin Arthritis Rheum2012;42:140-5. [PMID: 22494565] doi:10.1016/j.semarthrit.2012.02.008 CrossrefMedlineGoogle Scholar
    • 19. Lehtinen K Mortality and causes of death in 398 patients admitted to hospital with ankylosing spondylitis. Ann Rheum Dis1993;52:174-6. [PMID: 8484668] CrossrefMedlineGoogle Scholar
    • 20. Khan MA Khan MK Kushner I Survival among patients with ankylosing spondylitis: a life-table analysis. J Rheumatol1981;8:86-90. [PMID: 7218263] MedlineGoogle Scholar
    • 21. Zochling J Braun J Mortality in ankylosing spondylitis. Clin Exp Rheumatol2008;26:S80-4. [PMID: 19026148] MedlineGoogle Scholar
    • 22. Zochling J Braun J Mortality in rheumatoid arthritis and ankylosing spondylitis. Clin Exp Rheumatol2009;27:S127-30. [PMID: 19822059] MedlineGoogle Scholar
    • 23. Mok CC Kwok CL Ho LY Chan PT Yip SF Life expectancy, standardized mortality ratios, and causes of death in six rheumatic diseases in Hong Kong, China. Arthritis Rheum2011;63:1182-9. [PMID: 21391198] doi:10.1002/art.30277 CrossrefMedlineGoogle Scholar
    • 24. Bakland G Gran JT Nossent JC Increased mortality in ankylosing spondylitis is related to disease activity. Ann Rheum Dis2011;70:1921-5. [PMID: 21784726] doi:10.1136/ard.2011.151191 CrossrefMedlineGoogle Scholar
    • 25. Haroon N Inman RD Learch TJ Weisman MH Lee M Rahbar MH et alThe impact of tumor necrosis factor a inhibitors on radiographic progression in ankylosing spondylitis. Arthritis Rheum2013;65:2645-54. [PMID: 23818109] doi:10.1002/art.38070 CrossrefMedlineGoogle Scholar
    • 26. Baraliakos X Haibel H Listing J Sieper J Braun J Continuous long-term anti-TNF therapy does not lead to an increase in the rate of new bone formation over 8 years in patients with ankylosing spondylitis. Ann Rheum Dis2014;73:710-5. [PMID: 23505240] doi:10.1136/annrheumdis-2012-202698 CrossrefMedlineGoogle Scholar
    • 27. Williams JI Young W A summary of studies on the quality of health care administrative databases in Canada.. In: Goel V, Williams J, Anderson G, Blackstien-Hirsch P, Fooks C, Naylor D, eds. Patterns of Health Care in Ontario: The ICES Practice Atlas. 2d ed. Ottawa, ON, Canada: Canadian Med Assoc; 1996:339-45. Google Scholar
    • 28. Juurlink D Preyra C Croxford R Chong A Austin P Tu J et alCanadian Institute for Health Information Discharge Abstract Database: A Validation Study. Toronto, Ontario, Canada: Institute for Clinical Evaluative Sciences; 2006. Google Scholar
    • 29. Balzi D Barchielli A Battistella G Gnavi R Inio A Tessari R et al[Ischemic heart disease prevalence estimated using a standard algorithm based on electronic health data in various areas of Italy]. Epidemiol Prev2008;32:22-9. [PMID: 18928235] MedlineGoogle Scholar
    • 30. Roger VL Killian J Henkel M Weston SA Goraya TY Yawn BP et alCoronary disease surveillance in Olmsted County objectives and methodology. J Clin Epidemiol2002;55:593-601. [PMID: 12063101] CrossrefMedlineGoogle Scholar
    • 31. Wannamethee SG Shaper AG Lennon L Cardiovascular disease incidence and mortality in older men with diabetes and in men with coronary heart disease. Heart2004;90:1398-403. [PMID: 15547012] CrossrefMedlineGoogle Scholar
    • 32. Stavem K Rønning OM Survival of unselected stroke patients in a stroke unit compared with conventional care. QJM2002;95:143-52. [PMID: 11865169] CrossrefMedlineGoogle Scholar
    • 33. Tu K Campbell NR Chen ZL Cauch-Dudek KJ McAlister FA Accuracy of administrative databases in identifying patients with hypertension. Open Med2007;1:e18-26. [PMID: 20101286] MedlineGoogle Scholar
    • 34. Hux JE Ivis F Flintoft V Bica A Diabetes in Ontario: determination of prevalence and incidence using a validated administrative data algorithm. Diabetes Care2002;25:512-6. [PMID: 11874939] CrossrefMedlineGoogle Scholar
    • 35. Benchimol EI Guttmann A Mack DR Nguyen GC Marshall JK Gregor JC et alValidation of international algorithms to identify adults with inflammatory bowel disease in health administrative data from Ontario, Canada. J Clin Epidemiol2014;67:887-96. [PMID: 24774473] doi:10.1016/j.jclinepi.2014.02.019 CrossrefMedlineGoogle Scholar
    • 36. Shah BR Chiu M Amin S Ramani M Sadry S Tu JV Surname lists to identify South Asian and Chinese ethnicity from secondary data in Ontario, Canada: a validation study. BMC Med Res Methodol2010;10:42. [PMID: 20470433] doi:10.1186/1471-2288-10-42 CrossrefMedlineGoogle Scholar
    • 37. Elit L Saskin R Raut R Elliott L Murphy J Marrett L Sociodemographic factors associated with cervical cancer screening coverage and follow-up of high grade abnormal results in a population-based cohort. Gynecol Oncol2013;128:95-100. [PMID: 23085459] doi:10.1016/j.ygyno.2012.10.006 CrossrefMedlineGoogle Scholar
    • 38. Wilkins R PCCF+ Version 3G User's Guide (Geocodes/PCCF). Automated Geographic Coding Based on the Statistics Canada Postal Code Conversion Files, Including Postal Codes to June 2001. Ottawa, Ontario, Canada: Statistics Canada; 2001. Google Scholar
    • 39. Mamdani M Sykora K Li P Normand SL Streiner DL Austin PC et alReader's guide to critical appraisal of cohort studies: 2. Assessing potential for confounding. BMJ2005;330:960-2. [PMID: 15845982] CrossrefMedlineGoogle Scholar
    • 40. Thakkar B Hur K Henderson WG Oprian C A method to generate Kaplan-Meier and adjusted survival curves using SAS. In: Proceedings of the Twenty-Third Annual SAS Users Group International (SUGI) Conference; Nashville, Tennessee;. 22–25 March 1998:226-8. Google Scholar
    • 41. Margel D Urbach DR Lipscombe LL Bell CM Kulkarni G Austin PC et alMetformin use and all-cause and prostate cancer-specific mortality among men with diabetes. J Clin Oncol2013;31:3069-75. [PMID: 23918942] doi:10.1200/JCO.2012.46.7043 CrossrefMedlineGoogle Scholar
    • 42. Levy AR Szabo SM Rao SR Cifaldi M Maksymowych WP Estimating the occurrence of renal complications among persons with ankylosing spondylitis. Arthritis Care Res (Hoboken)2014;66:440-5. [PMID: 24106183] doi:10.1002/acr.22176 CrossrefMedlineGoogle Scholar
    • 43. Wallis D Haroon N Ayearst R Carty A Inman RD Ankylosing spondylitis and nonradiographic axial spondyloarthritis: part of a common spectrum or distinct diseases? J Rheumatol2013;40:2038-41. [PMID: 24187102] doi:10.3899/jrheum.130588 CrossrefMedlineGoogle Scholar
    • 44. Tournadre A Pereira B Lhoste A Dubost JJ Ristori JM Claudepierre P et alDifferences between women and men with recent-onset axial spondyloarthritis: results from a prospective multicenter French cohort. Arthritis Care Res (Hoboken)2013;65:1482-9. [PMID: 23463610] doi:10.1002/acr.22001 CrossrefMedlineGoogle Scholar
    • 45. Radford EP Doll R Smith PG Mortality among patients with ankylosing spondylitis not given X-ray therapy. N Engl J Med1977;297:572-6. [PMID: 887115] CrossrefMedlineGoogle Scholar
    • 46. Kaprove RE Little AH Graham DC Rosen PS Ankylosing spondylitis: survival in men with and without radiotherapy. Arthritis Rheum1980;23:57-61. [PMID: 7352944] CrossrefMedlineGoogle Scholar
    • 47. Schisterman EF Cole SR Platt RW Overadjustment bias and unnecessary adjustment in epidemiologic studies. Epidemiology2009;20:488-95. [PMID: 19525685] doi:10.1097/EDE.0b013e3181a819a1 CrossrefMedlineGoogle Scholar
    • 48. Hamdi W ChelliBouaziz M Zouch I Ghannouchi MM Haouel M Ladeb MF et alAssessment of preclinical atherosclerosis in patients with ankylosing spondylitis. J Rheumatol2012;39:322-6. [PMID: 22247364] doi:10.3899/jrheum.110792 CrossrefMedlineGoogle Scholar
    • 49. Papadakis JA Sidiropoulos PI Karvounaris SA Vrentzos GE Spanakis EK Ganotakis ES et alHigh prevalence of metabolic syndrome and cardiovascular risk factors in men with ankylosing spondylitis on anti-TNFα treatment: correlation with disease activity. Clin Exp Rheumatol2009;27:292-8. [PMID: 19473571] MedlineGoogle Scholar
    • 50. Chen HH Yeh SY Chen HY Lin CL Sung FC Kao CH Ankylosing spondylitis and other inflammatory spondyloarthritis increase the risk of developing type 2 diabetes in an Asian population. Rheumatol Int2014;34:265-70. [PMID: 24362789] doi:10.1007/s00296-013-2927-5 CrossrefMedlineGoogle Scholar
    • 51. Kanathur N Lee-Chiong T Pulmonary manifestations of ankylosing spondylitis. Clin Chest Med2010;31:547-54. [PMID: 20692546] doi:10.1016/j.ccm.2010.05.002 CrossrefMedlineGoogle Scholar
    • 52. Reveille JD Hirsch R Dillon CF Carroll MD Weisman MH The prevalence of HLA-B27 in the US: data from the US National Health and Nutrition Examination Survey, 2009. Arthritis Rheum2012;64:1407-11. [PMID: 22139851] doi:10.1002/art.33503 CrossrefMedlineGoogle Scholar
    • 53. Bhala N Emberson J Merhi A Abramson S Arber N Baron JA et alCoxib and traditional NSAID Trialists' (CNT) CollaborationVascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet2013;382:769-79. [PMID: 23726390] doi:10.1016/S0140-6736(13)60900-9 CrossrefMedlineGoogle Scholar
    • 54. Watson DJ Rhodes T Cai B Guess HA Lower risk of thromboembolic cardiovascular events with naproxen among patients with rheumatoid arthritis. Arch Intern Med2002;162:1105-10. [PMID: 12020179] CrossrefMedlineGoogle Scholar
    • 55. Lindhardsen J Gislason GH Jacobsen S Ahlehoff O Olsen AM Madsen OR et alNon-steroidal anti-inflammatory drugs and risk of cardiovascular disease in patients with rheumatoid arthritis: a nationwide cohort study. Ann Rheum Dis2013. [PMID: 23749610] CrossrefMedlineGoogle Scholar
    • 56. Singh JA Holmgren AR Krug H Noorbaloochi S Accuracy of the diagnoses of spondylarthritides in veterans affairs medical center databases. Arthritis Rheum2007;57:648-55. [PMID: 17471541] CrossrefMedlineGoogle Scholar
    • 57. Poddubnyy D Haibel H Listing J Märker-Hermann E Zeidler H Braun J et alBaseline radiographic damage, elevated acute-phase reactant levels, and cigarette smoking status predict spinal radiographic progression in early axial spondylarthritis. Arthritis Rheum2012;64:1388-98. [PMID: 22127957] doi:10.1002/art.33465 CrossrefMedlineGoogle Scholar