Original Research
15 September 2015

Patients With Ankylosing Spondylitis Have Increased Cardiovascular and Cerebrovascular Mortality: A Population-Based Study

Publication: Annals of Internal Medicine
Volume 163, Number 6

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.

Get full access to this article

View all available purchase options and get full access to this article.

References

1.
Azevedo VFPecoits-Filho R. Atherosclerosis and endothelial dysfunction in patients with ankylosing spondylitis. Rheumatol Int. 2010;30:1411-6. [PMID: 20349072]  doi: 10.1007/s00296-010-1416-3
2.
Vallance PCollier JBhagat K. Infection, inflammation, and infarction: does acute endothelial dysfunction provide a link? Lancet. 1997;349:1391-2. [PMID: 9149715]
3.
Boring LGosling JCleary MCharo IF. Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature. 1998;394:894-7. [PMID: 9732872]
4.
Gu LOkada YClinton SKGerard CSukhova GKLibby Pet al. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell. 1998;2:275-81. [PMID: 9734366]
5.
Bodnár NKerekes GSeres IParagh GKappelmayer JNémethné ZGet al. Assessment of subclinical vascular disease associated with ankylosing spondylitis. J Rheumatol. 2011;38:723-9. [PMID: 21239756]  doi: 10.3899/jrheum.100668
6.
Mathieu SJoly HBaron GTournadre ADubost JJRistori JMet al. Trend 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
7.
Papagoras CVoulgari PVDrosos AA. Atherosclerosis and cardiovascular disease in the spondyloarthritides, particularly ankylosing spondylitis and psoriatic arthritis. Clin Exp Rheumatol. 2013;31:612-20. [PMID: 23406817]
8.
Peters MJvanEijk ICSmulders YMSerne EDijkmans BAvan der Horst-Bruinsma IEet al. Signs of accelerated preclinical atherosclerosis in patients with ankylosing spondylitis. J Rheumatol. 2010;37:161-6. [PMID: 19955053]  doi: 10.3899/jrheum.090667
9.
Sari IOkan TAkar SCece HAltay CSecil Met al. Impaired endothelial function in patients with ankylosing spondylitis. Rheumatology (Oxford). 2006;45:283-6. [PMID: 16204374]
10.
van Eijk ICPeters MJSerné EHvan der Horst-Bruinsma IEDijkmans BASmulders YMet al. Microvascular function is impaired in ankylosing spondylitis and improves after tumour necrosis factor alpha blockade. Ann Rheum Dis. 2009;68:362-6. [PMID: 18390569]  doi: 10.1136/ard.2007.086777
11.
Szabo SMLevy ARRao SRKirbach SELacaille DCifaldi Met al. Increased risk of cardiovascular and cerebrovascular diseases in individuals with ankylosing spondylitis: a population-based study. Arthritis Rheum. 2011;63:3294-304. [PMID: 21834064]  doi: 10.1002/art.30581
12.
Vinsonneau UBrondex AMansourati JSaraux ACornily JCArlès Fet al. Cardiovascular disease in patients with spondyloarthropathies. Joint Bone Spine. 2008;75:18-21. [PMID: 17913549]
13.
Lautermann DBraun J. Ankylosing spondylitis—cardiac manifestations. Clin Exp Rheumatol. 2002;20:S11-5. [PMID: 12463440]
14.
Dik VKPeters MJDijkmans PAVan der Weijden MADeVries MKDijkmans BAet al. The relationship between disease-related characteristics and conduction disturbances in ankylosing spondylitis. Scand J Rheumatol. 2010;39:38-41. [PMID: 20132069]  doi: 10.3109/03009740903096101
15.
Peters MJVisman INielen MMVanDillen NVerheij RAvan der Horst-Bruinsma IEet al. Ankylosing spondylitis: a risk factor for myocardial infarction? Ann Rheum Dis. 2010;69:579-81. [PMID: 19403516]  doi: 10.1136/ard.2009.110593
16.
Huang YPWang YHPan SL. Increased risk of ischemic heart disease in young patients with newly diagnosed ankylosing spondylitis—a population-based longitudinal follow-up study. PLoS One. 2013;8:e64155. [PMID: 23691161]  doi: 10.1371/journal.pone.0064155
17.
Hollan ISaatvedt KAlmdahl SMMikkelsen KMoer RHalvorsen Pet al. Spondyloarthritis: a strong predictor of early coronary artery bypass grafting. Scand J Rheumatol. 2008;37:18-22. [PMID: 18189190]  doi: 10.1080/03009740701716868
18.
Brophy SCooksey RAtkinson MZhou SMHusain MJMacey Set al. No increased rate of acute myocardial infarction or stroke among patients with ankylosing spondylitis-a retrospective cohort study using routine data. Semin Arthritis Rheum. 2012;42:140-5. [PMID: 22494565]  doi: 10.1016/j.semarthrit.2012.02.008
19.
Lehtinen K. Mortality and causes of death in 398 patients admitted to hospital with ankylosing spondylitis. Ann Rheum Dis. 1993;52:174-6. [PMID: 8484668]
20.
Khan MAKhan MKKushner I. Survival among patients with ankylosing spondylitis: a life-table analysis. J Rheumatol. 1981;8:86-90. [PMID: 7218263]
21.
Zochling JBraun J. Mortality in ankylosing spondylitis. Clin Exp Rheumatol. 2008;26:S80-4. [PMID: 19026148]
22.
Zochling JBraun J. Mortality in rheumatoid arthritis and ankylosing spondylitis. Clin Exp Rheumatol. 2009;27:S127-30. [PMID: 19822059]
23.
Mok CCKwok CLHo LYChan PTYip SF. Life expectancy, standardized mortality ratios, and causes of death in six rheumatic diseases in Hong Kong, China. Arthritis Rheum. 2011;63:1182-9. [PMID: 21391198]  doi: 10.1002/art.30277
24.
Bakland GGran JTNossent JC. Increased mortality in ankylosing spondylitis is related to disease activity. Ann Rheum Dis. 2011;70:1921-5. [PMID: 21784726]  doi: 10.1136/ard.2011.151191
25.
Haroon NInman RDLearch TJWeisman MHLee MRahbar MHet al. The impact of tumor necrosis factor a inhibitors on radiographic progression in ankylosing spondylitis. Arthritis Rheum. 2013;65:2645-54. [PMID: 23818109]  doi: 10.1002/art.38070
26.
Baraliakos XHaibel HListing JSieper JBraun 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 Dis. 2014;73:710-5. [PMID: 23505240]  doi: 10.1136/annrheumdis-2012-202698
27.
Williams JIYoung 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.
28.
Juurlink DPreyra CCroxford RChong AAustin PTu Jet al. Canadian Institute for Health Information Discharge Abstract Database: A Validation Study. Toronto, Ontario, Canada: Institute for Clinical Evaluative Sciences; 2006.
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 Prev. 2008;32:22-9. [PMID: 18928235]
30.
Roger VLKillian JHenkel MWeston SAGoraya TYYawn BPet al. Coronary disease surveillance in Olmsted County objectives and methodology. J Clin Epidemiol. 2002;55:593-601. [PMID: 12063101]
31.
Wannamethee SGShaper AGLennon L. Cardiovascular disease incidence and mortality in older men with diabetes and in men with coronary heart disease. Heart. 2004;90:1398-403. [PMID: 15547012]
32.
Stavem KRønning OM. Survival of unselected stroke patients in a stroke unit compared with conventional care. QJM. 2002;95:143-52. [PMID: 11865169]
33.
Tu KCampbell NRChen ZLCauch-Dudek KJMcAlister FA. Accuracy of administrative databases in identifying patients with hypertension. Open Med. 2007;1:e18-26. [PMID: 20101286]
34.
Hux JEIvis FFlintoft VBica A. Diabetes in Ontario: determination of prevalence and incidence using a validated administrative data algorithm. Diabetes Care. 2002;25:512-6. [PMID: 11874939]
35.
Benchimol EIGuttmann AMack DRNguyen GCMarshall JKGregor JCet al. Validation of international algorithms to identify adults with inflammatory bowel disease in health administrative data from Ontario, Canada. J Clin Epidemiol. 2014;67:887-96. [PMID: 24774473]  doi: 10.1016/j.jclinepi.2014.02.019
36.
Shah BRChiu MAmin SRamani MSadry STu JV. Surname lists to identify South Asian and Chinese ethnicity from secondary data in Ontario, Canada: a validation study. BMC Med Res Methodol. 2010;10:42. [PMID: 20470433]  doi: 10.1186/1471-2288-10-42
37.
Elit LSaskin RRaut RElliott LMurphy JMarrett L. Sociodemographic factors associated with cervical cancer screening coverage and follow-up of high grade abnormal results in a population-based cohort. Gynecol Oncol. 2013;128:95-100. [PMID: 23085459]  doi: 10.1016/j.ygyno.2012.10.006
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.
39.
Mamdani MSykora KLi PNormand SLStreiner DLAustin PCet al. Reader's guide to critical appraisal of cohort studies: 2. Assessing potential for confounding. BMJ. 2005;330:960-2. [PMID: 15845982]
40.
Thakkar BHur KHenderson WGOprian 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.
41.
Margel DUrbach DRLipscombe LLBell CMKulkarni GAustin PCet al. Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes. J Clin Oncol. 2013;31:3069-75. [PMID: 23918942]  doi: 10.1200/JCO.2012.46.7043
42.
Levy ARSzabo SMRao SRCifaldi MMaksymowych 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
43.
Wallis DHaroon NAyearst RCarty AInman RD. Ankylosing spondylitis and nonradiographic axial spondyloarthritis: part of a common spectrum or distinct diseases? J Rheumatol. 2013;40:2038-41. [PMID: 24187102]  doi: 10.3899/jrheum.130588
44.
Tournadre APereira BLhoste ADubost JJRistori JMClaudepierre Pet al. Differences 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
45.
Radford EPDoll RSmith PG. Mortality among patients with ankylosing spondylitis not given X-ray therapy. N Engl J Med. 1977;297:572-6. [PMID: 887115]
46.
Kaprove RELittle AHGraham DCRosen PS. Ankylosing spondylitis: survival in men with and without radiotherapy. Arthritis Rheum. 1980;23:57-61. [PMID: 7352944]
47.
Schisterman EFCole SRPlatt RW. Overadjustment bias and unnecessary adjustment in epidemiologic studies. Epidemiology. 2009;20:488-95. [PMID: 19525685]  doi: 10.1097/EDE.0b013e3181a819a1
48.
Hamdi WChelliBouaziz MZouch IGhannouchi MMHaouel MLadeb MFet al. Assessment of preclinical atherosclerosis in patients with ankylosing spondylitis. J Rheumatol. 2012;39:322-6. [PMID: 22247364]  doi: 10.3899/jrheum.110792
49.
Papadakis JASidiropoulos PIKarvounaris SAVrentzos GESpanakis EKGanotakis ESet al. High prevalence of metabolic syndrome and cardiovascular risk factors in men with ankylosing spondylitis on anti-TNFα treatment: correlation with disease activity. Clin Exp Rheumatol. 2009;27:292-8. [PMID: 19473571]
50.
Chen HHYeh SYChen HYLin CLSung FCKao CH. Ankylosing spondylitis and other inflammatory spondyloarthritis increase the risk of developing type 2 diabetes in an Asian population. Rheumatol Int. 2014;34:265-70. [PMID: 24362789]  doi: 10.1007/s00296-013-2927-5
51.
Kanathur NLee-Chiong T. Pulmonary manifestations of ankylosing spondylitis. Clin Chest Med. 2010;31:547-54. [PMID: 20692546]  doi: 10.1016/j.ccm.2010.05.002
52.
Reveille JDHirsch RDillon CFCarroll MDWeisman MH. The prevalence of HLA-B27 in the US: data from the US National Health and Nutrition Examination Survey, 2009. Arthritis Rheum. 2012;64:1407-11. [PMID: 22139851]  doi: 10.1002/art.33503
53.
Bhala NEmberson JMerhi AAbramson SArber NBaron JAet alCoxib and traditional NSAID Trialists' (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382:769-79. [PMID: 23726390]  doi: 10.1016/S0140-6736(13)60900-9
54.
Watson DJRhodes TCai BGuess HA. Lower risk of thromboembolic cardiovascular events with naproxen among patients with rheumatoid arthritis. Arch Intern Med. 2002;162:1105-10. [PMID: 12020179]
55.
Lindhardsen JGislason GHJacobsen SAhlehoff OOlsen AMMadsen ORet al. Non-steroidal anti-inflammatory drugs and risk of cardiovascular disease in patients with rheumatoid arthritis: a nationwide cohort study. Ann Rheum Dis. 2013. [PMID: 23749610]
56.
Singh JAHolmgren ARKrug HNoorbaloochi S. Accuracy of the diagnoses of spondylarthritides in veterans affairs medical center databases. Arthritis Rheum. 2007;57:648-55. [PMID: 17471541]
57.
Poddubnyy DHaibel HListing JMärker-Hermann EZeidler HBraun Jet al. Baseline radiographic damage, elevated acute-phase reactant levels, and cigarette smoking status predict spinal radiographic progression in early axial spondylarthritis. Arthritis Rheum. 2012;64:1388-98. [PMID: 22127957]  doi: 10.1002/art.33465

Information & Authors

Information

Published In

cover image Annals of Internal Medicine
Annals of Internal Medicine
Volume 163Number 615 September 2015
Pages: 409 - 416

History

Published online: 15 September 2015
Published in issue: 15 September 2015

Keywords

Authors

Affiliations

Nisha Nigil Haroon, MD, DM, DNB, MSc
From the University of Toronto; Institute for Clinical Evaluative Sciences; Institute of Health Policy, Management and Evaluation; University Health Network; and Toronto Western Research Institute, Toronto, and McMaster University, Hamilton, Ontario, Canada.
J. Michael Paterson, MSc
From the University of Toronto; Institute for Clinical Evaluative Sciences; Institute of Health Policy, Management and Evaluation; University Health Network; and Toronto Western Research Institute, Toronto, and McMaster University, Hamilton, Ontario, Canada.
Ping Li, PhD
From the University of Toronto; Institute for Clinical Evaluative Sciences; Institute of Health Policy, Management and Evaluation; University Health Network; and Toronto Western Research Institute, Toronto, and McMaster University, Hamilton, Ontario, Canada.
Robert D. Inman, MD
From the University of Toronto; Institute for Clinical Evaluative Sciences; Institute of Health Policy, Management and Evaluation; University Health Network; and Toronto Western Research Institute, Toronto, and McMaster University, Hamilton, Ontario, Canada.
Nigil Haroon, MD, PhD, DM
From the University of Toronto; Institute for Clinical Evaluative Sciences; Institute of Health Policy, Management and Evaluation; University Health Network; and Toronto Western Research Institute, Toronto, and McMaster University, Hamilton, Ontario, Canada.
Disclaimer: The opinions, results, and conclusions reported in this article are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario Ministry of Health and Long-Term Care is intended or should be inferred. Parts of this material are based on data and information compiled and provided by CIHI; however, the analyses, conclusions, opinions, and statements expressed herein are those of the authors and not necessarily those of CIHI.
Grant Support: By the Arthritis Center of Excellence; The Arthritis Society; and ICES, which is funded by a grant from the Ontario Ministry of Health and Long-Term Care.
Disclosures: Dr. N. Haroon reports grants from the Arthritis Society, nonfinancial support from the Institute of Clinical Evaluative Sciences, and grants from Toronto General and Western Hospital Foundation during the conduct of the study and personal fees from AbbVie, Amgen, Celgene, Janssen, UCB, and Hospira outside the submitted work. Authors not named here have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=M14-2470.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.
Reproducible Research Statement: Study protocol and statistical code: Available from Dr. Nigil Haroon (e-mail, [email protected]). Data set: Not available.
Corresponding Author: Nigil Haroon, MD, PhD, DM, Toronto Western Hospital, 1E-425, 399 Bathurst Street, Toronto Western Hospital, Toronto, Ontario M5T 2S8, Canada; e-mail, [email protected].
Current Author Addresses: Dr. N.N. Haroon: Department of Medicine, University of Toronto, 200 Elizabeth Street, 7th Floor, OP Program, Toronto, Ontario M5G 2C4, Canada.
Mr. Paterson and Dr. Li: Institute for Clinical Evaluative Sciences, G106-2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
Dr. Inman: Toronto Western Hospital, 1EW-423, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada.
Dr. N. Haroon: Toronto Western Hospital, 1EW-425, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada.
Author Contributions: Conception and design: N.N. Haroon, J.M. Paterson, P. Li, R.D. Inman, N. Haroon.
Analysis and interpretation of the data: N.N. Haroon, J.M. Paterson, P. Li, R.D. Inman, N. Haroon.
Drafting of the article: N.N. Haroon, R.D. Inman, N. Haroon.
Critical revision of the article for important intellectual content: N.N. Haroon, J.M. Paterson, P. Li, R.D. Inman, N. Haroon.
Final approval of the article: N.N. Haroon, J.M. Paterson, R.D. Inman, N. Haroon.
Statistical expertise: N.N. Haroon, P. Li, N. Haroon.
Obtaining of funding: R.D. Inman, N. Haroon.
Administrative, technical, or logistic support: J.M. Paterson, P. Li, R.D. Inman.
This article was published online first at www.annals.org on 11 August 2015.

Metrics & Citations

Metrics

Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. For an editable text file, please select Medlars format which will download as a .txt file. Simply select your manager software from the list below and click Download.

For more information or tips please see 'Downloading to a citation manager' in the Help menu.

Format





Download article citation data for:
Nisha Nigil Haroon, J. Michael Paterson, Ping Li, et al. Patients With Ankylosing Spondylitis Have Increased Cardiovascular and Cerebrovascular Mortality: A Population-Based Study. Ann Intern Med.2015;163:409-416. [Epub 15 September 2015]. doi:10.7326/M14-2470

View More

Get Access

Login Options:
Purchase

You will be redirected to acponline.org to sign-in to Annals to complete your purchase.

Create your Free Account

You will be redirected to acponline.org to create an account that will provide access to Annals.

View options

PDF/ePub

View PDF/ePub

Related in ACP Journals

Full Text

View Full Text

Media

Figures

Other

Tables

Share

Share

Copy the content Link

Share on social media