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

    Abstract

    Background:

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

    Objective:

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

    Design:

    Population-based retrospective cohort study using administrative health data.

    Setting:

    Ontario, Canada.

    Patients:

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

    Measurements:

    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.

    Results:

    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.

    Limitation:

    Diagnosis codes for AS were not validated in Ontario.

    Conclusion:

    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.

    References

    • 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