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

Nisha Nigil Haroon, MD, DM, DNB, MSc; J. Michael Paterson, MSc; Ping Li, PhD; Robert D. Inman, MD; and Nigil Haroon, MD, PhD, DM
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This article was published online first at www.annals.org on 11 August 2015.

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, Nigil.haroon@uhn.ca). Data set: Not available.

Requests for Single Reprints: Nigil Haroon, MD, PhD, DM, Toronto Western Hospital, 1E-425, 399 Bathurst Street, Toronto Western Hospital, Toronto, Ontario M5T 2S8, Canada; e-mail, Nigil.Haroon@uhn.ca.

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.

Ann Intern Med. 2015;163(6):409-416. doi:10.7326/M14-2470
Text Size: A A A

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.


Grahic Jump Location
Figure 1.

Adjusted Kaplan–Meier curve showing differences in survival among patients with AS and comparators due to vascular events.

The curve shows significantly higher vascular mortality in patients with AS versus matched comparators without AS. The log-rank test was significant (P < 0.001). The curve is adjusted for the following baseline variables: chronic kidney disease, peripheral vascular disease, hypertension, inflammatory bowel disease, diabetes, dementia, and cancer. AS = ankylosing spondylitis.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Hazard ratio plot showing risk factors for vascular mortality among all study patients with ankylosing spondylitis (top) and the subgroup of patients aged 66 years or older (bottom).

The association with medications is also shown in the bottom plot. CKD = chronic kidney disease; COX-2 = cyclooxygenase-2; IBD = inflammatory bowel disease; NSAID = nonsteroidal anti-inflammatory drug; PVD = peripheral vascular disease.

Grahic Jump Location




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Submit a Comment/Letter
Patients with ankylosing spondylitis should periodically be screened for both overt and subclinical atherosclerotic cardiovascular diseases and preventive statin therapy may be considered
Posted on August 31, 2015
Gauranga Dhar
Bangladesh Institute of Family Medicine and Research
Conflict of Interest: None Declared
Patients with both rheumatoid arthritis (RA) and ankylosing spondylitis (AS) [1] are in increased risk of vascular morbidity and mortality. Statin use is associated with 21% decreased risk of cardiovascular events in patients with RA [2] irrespective of lipid parameters because pro-inflammatory cytokines lead to endothelial dysfunction and increased atherosclerotic process and higher cardiovascular mortality. In contrast to rheumatoid arthritis which is usually found in middle aged persons, onset of ankylosing spondylitis, starts at much earlier ages; 20-30 years of age. At this age, importance of vascular complications is usually ignored.
Ankylosing spondylitis is a genetically predisposed, chronic-inflammatory disease associated with increased pro-inflammatory cytokines; TNF-alpha, TGF-beta and IL-1. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) may be elevated but normal CRP and ESR do not rule out the diagnosis of AS [3].
AS is associated with increase in blood pressure and dyslipidemia may lead to congestive heart failure and peripheral arterial disease [4]. Carotid intima media thickness (CIMT), a marker of subclinical atherosclerosis can be found in significant number of patients with AS [5][6].
Since AS is a life-long disease, along with NSAIDs, DMARDs, physiotherapy and or biologic, periodic cardiovascular risk assessment and statin therapy is required [7].

1. Nisha Nigil Haroon, MD, DM, DNB, MSc; J. Michael Paterson, MSc; Ping Li, PhD; Robert D. Inman, MD; and Nigil Haroon, MD, PhD, DM. Patients With Ankylosing Spondylitis Have Increased Cardiovascular and Cerebrovascular Mortality: A Population-based Study. Ann Intern Med. Published online 11 August 2015
2. Schoenfeld SR, Lu L, Rai SK, Seeger JD, Zhang Y, Choi HK. Statin use and mortality in rheumatoid arthritis: a general population-based cohort study. Ann Rheum Dis. 2015 Aug 5
3. Spoorenberg A, van der Heijde D, de Klerk E, et al. Relative value of erythrocyte sedimentation rate and C-reactive protein in assessment of disease activity in ankylosing spondylitis. J Rheumatol. 1999;26:980-984
4. Han C, Robinson DW Jr, Hackett MV, Paramore LC, Fraeman KH, Bala MV. Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. J Rheumatol. 2006; 33: 2167–2172
5. Gonzalez-Gay MA, Gonzalez-Juanatey C, Piñeiro A, et al. High-grade C-reactive protein elevation correlates with accelerated atherogenesis in patients with rheumatoid arthritis. J Rheumatol. 2005;32(7):1219-23.
6. Carotid intima-media thickness in spondyloarthritis patients. Sao Paulo Med. J. vol.131 no.2 São Paulo 2013
7. Van Denderen, J C et al. “Statin Therapy Might Be Beneficial for Patients with Ankylosing Spondylitis.” Annals of the Rheumatic Diseases 65.5 (2006): 695–696. PMC. Web. 31 Aug. 2015.
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Summary for Patients

Cardiovascular and Cerebrovascular Mortality Are Increased in Ankylosing Spondylitis

The full report is titled “Patients With Ankylosing Spondylitis Have Increased Cardiovascular and Cerebrovascular Mortality. A Population-Based Study.” It is in the 15 September 2015 issue of Annals of Internal Medicine (volume 163, pages 409-416). The authors are N.N. Haroon, J.M. Paterson, P. Li, R.D. Inman, and N. Haroon.


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