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 VFPecoits-Filho RAtherosclerosis 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 PCollier JBhagat KInfection, inflammation, and infarction: does acute endothelial dysfunction provide a link? Lancet1997;349:1391-2. [PMID: 9149715] CrossrefMedlineGoogle Scholar
    • 3. Boring LGosling JCleary MCharo IFDecreased 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 LOkada YClinton SKGerard CSukhova GKLibby Pet 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 NKerekes GSeres IParagh GKappelmayer JNémethné ZGet 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 SJoly HBaron GTournadre ADubost JJRistori JMet 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 CVoulgari PVDrosos AAAtherosclerosis and cardiovascular disease in the spondyloarthritides, particularly ankylosing spondylitis and psoriatic arthritis. Clin Exp Rheumatol2013;31:612-20. [PMID: 23406817] MedlineGoogle Scholar
    • 8. Peters MJvanEijk ICSmulders YMSerne EDijkmans BAvan der Horst-Bruinsma IEet 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 IOkan TAkar SCece HAltay CSecil Met alImpaired endothelial function in patients with ankylosing spondylitis. Rheumatology (Oxford)2006;45:283-6. [PMID: 16204374] CrossrefMedlineGoogle Scholar
    • 10. van Eijk ICPeters MJSerné EHvan der Horst-Bruinsma IEDijkmans BASmulders YMet 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 SMLevy ARRao SRKirbach SELacaille DCifaldi Met 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 UBrondex AMansourati JSaraux ACornily JCArlès Fet alCardiovascular disease in patients with spondyloarthropathies. Joint Bone Spine2008;75:18-21. [PMID: 17913549] CrossrefMedlineGoogle Scholar
    • 13. Lautermann DBraun JAnkylosing spondylitis—cardiac manifestations. Clin Exp Rheumatol2002;20:S11-5. [PMID: 12463440] MedlineGoogle Scholar
    • 14. Dik VKPeters MJDijkmans PAVan der Weijden MADeVries MKDijkmans BAet 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 MJVisman INielen MMVanDillen NVerheij RAvan der Horst-Bruinsma IEet 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 YPWang YHPan SLIncreased 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 ISaatvedt KAlmdahl SMMikkelsen KMoer RHalvorsen Pet 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 SCooksey RAtkinson MZhou SMHusain MJMacey Set 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 KMortality 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 MAKhan MKKushner ISurvival among patients with ankylosing spondylitis: a life-table analysis. J Rheumatol1981;8:86-90. [PMID: 7218263] MedlineGoogle Scholar
    • 21. Zochling JBraun JMortality in ankylosing spondylitis. Clin Exp Rheumatol2008;26:S80-4. [PMID: 19026148] MedlineGoogle Scholar
    • 22. Zochling JBraun JMortality in rheumatoid arthritis and ankylosing spondylitis. Clin Exp Rheumatol2009;27:S127-30. [PMID: 19822059] MedlineGoogle Scholar
    • 23. Mok CCKwok CLHo LYChan PTYip SFLife 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 GGran JTNossent JCIncreased 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 NInman RDLearch TJWeisman MHLee MRahbar MHet 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 XHaibel HListing JSieper JBraun JContinuous 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 JIYoung WA 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 DPreyra CCroxford RChong AAustin PTu Jet alCanadian Institute for Health Information Discharge Abstract Database: A Validation Study. Toronto, Ontario, Canada: Institute for Clinical Evaluative Sciences; 2006. Google Scholar
    • 29. Balzi DBarchielli ABattistella GGnavi RInio ATessari Ret 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 VLKillian JHenkel MWeston SAGoraya TYYawn BPet alCoronary disease surveillance in Olmsted County objectives and methodology. J Clin Epidemiol2002;55:593-601. [PMID: 12063101] CrossrefMedlineGoogle Scholar
    • 31. Wannamethee SGShaper AGLennon LCardiovascular 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 KRønning OMSurvival of unselected stroke patients in a stroke unit compared with conventional care. QJM2002;95:143-52. [PMID: 11865169] CrossrefMedlineGoogle Scholar
    • 33. Tu KCampbell NRChen ZLCauch-Dudek KJMcAlister FAAccuracy of administrative databases in identifying patients with hypertension. Open Med2007;1:e18-26. [PMID: 20101286] MedlineGoogle Scholar
    • 34. Hux JEIvis FFlintoft VBica ADiabetes in Ontario: determination of prevalence and incidence using a validated administrative data algorithm. Diabetes Care2002;25:512-6. [PMID: 11874939] CrossrefMedlineGoogle Scholar
    • 35. Benchimol EIGuttmann AMack DRNguyen GCMarshall JKGregor JCet 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 BRChiu MAmin SRamani MSadry STu JVSurname 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 LSaskin RRaut RElliott LMurphy JMarrett LSociodemographic 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 RPCCF+ 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 MSykora KLi PNormand SLStreiner DLAustin PCet alReader's guide to critical appraisal of cohort studies: 2. Assessing potential for confounding. BMJ2005;330:960-2. [PMID: 15845982] CrossrefMedlineGoogle Scholar
    • 40. Thakkar BHur KHenderson WGOprian CA 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 DUrbach DRLipscombe LLBell CMKulkarni GAustin PCet 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 ARSzabo SMRao SRCifaldi MMaksymowych WPEstimating 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 DHaroon NAyearst RCarty AInman RDAnkylosing 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 APereira BLhoste ADubost JJRistori JMClaudepierre Pet 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 EPDoll RSmith PGMortality among patients with ankylosing spondylitis not given X-ray therapy. N Engl J Med1977;297:572-6. [PMID: 887115] CrossrefMedlineGoogle Scholar
    • 46. Kaprove RELittle AHGraham DCRosen PSAnkylosing spondylitis: survival in men with and without radiotherapy. Arthritis Rheum1980;23:57-61. [PMID: 7352944] CrossrefMedlineGoogle Scholar
    • 47. Schisterman EFCole SRPlatt RWOveradjustment bias and unnecessary adjustment in epidemiologic studies. Epidemiology2009;20:488-95. [PMID: 19525685] doi:10.1097/EDE.0b013e3181a819a1 CrossrefMedlineGoogle Scholar
    • 48. Hamdi WChelliBouaziz MZouch IGhannouchi MMHaouel MLadeb MFet 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 JASidiropoulos PIKarvounaris SAVrentzos GESpanakis EKGanotakis ESet 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 HHYeh SYChen HYLin CLSung FCKao CHAnkylosing 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 NLee-Chiong TPulmonary manifestations of ankylosing spondylitis. Clin Chest Med2010;31:547-54. [PMID: 20692546] doi:10.1016/j.ccm.2010.05.002 CrossrefMedlineGoogle Scholar
    • 52. Reveille JDHirsch RDillon CFCarroll MDWeisman MHThe 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 NEmberson JMerhi AAbramson SArber NBaron JAet 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 DJRhodes TCai BGuess HALower risk of thromboembolic cardiovascular events with naproxen among patients with rheumatoid arthritis. Arch Intern Med2002;162:1105-10. [PMID: 12020179] CrossrefMedlineGoogle Scholar
    • 55. Lindhardsen JGislason GHJacobsen SAhlehoff OOlsen AMMadsen ORet 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 JAHolmgren ARKrug HNoorbaloochi SAccuracy of the diagnoses of spondylarthritides in veterans affairs medical center databases. Arthritis Rheum2007;57:648-55. [PMID: 17471541] CrossrefMedlineGoogle Scholar
    • 57. Poddubnyy DHaibel HListing JMärker-Hermann EZeidler HBraun Jet 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