Cardiovascular morbidity and mortality in ankylosing spondylitis and psoriatic arthritis

Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx

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Cardiovascular morbidity and mortality in ankylosing spondylitis and psoriatic arthritis Jean W. Liew a, Sofia Ramiro b, Lianne S. Gensler c, * a b c

University of Washington, 1959 NE Pacific St, BB561, Seattle, 98195, WA, USA Leiden University Medical Center, Leiden, 2333 ZA, the Netherlands University of California, San Francisco, 400 Parnassus Ave, Box 0326, San Francisco, 94143-0326, CA, USA

a b s t r a c t Keywords: Ankylosing spondylitis Axial spondyloarthritis Psoriatic arthritis Cardiovascular disease Atherosclerosis Arrhythmias Aortic root

The cardiovascular burden in inflammatory rheumatic diseases is well recognized. Recently, this burden has been highlighted in ankylosing spondylitis (also known as radiographic axial spondyloarthritis) and psoriatic arthritis. We review the cardiovascular morbidity and mortality in these diseases, as well as the prevalence and incidence of traditional cardiovascular risk factors. We examine the contribution of anti-inflammatory therapy with nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, and TNF inhibitors on the cardiovascular risk profile. Finally, we examine the available recommendations for the management of cardiovascular comorbidity, as they apply to the spondyloarthritis population. © 2019 Published by Elsevier Ltd.

Introduction Cardiovascular disease (CVD) is the leading cause of death in many parts of the developed world. The evidence for increased CVD burden and cardiovascular (CV) risk in patients with inflammatory rheumatic diseases is well recognized [1]. The European League Against Rheumatism (EULAR) recently updated the recommendations for CVD risk management in inflammatory rheumatic diseases, although the evidence base was strongest for rheumatoid arthritis (RA) [2]. In spondyloarthritis (SpA), the evidence in patients with axial disease is typically limited to those with evidence of radiographic

* Corresponding author. E-mail addresses: [email protected] (J.W. Liew), sofi[email protected] (S. Ramiro), [email protected] (L.S. Gensler). https://doi.org/10.1016/j.berh.2019.01.002 1521-6942/© 2019 Published by Elsevier Ltd.

Please cite this article as: Liew JW et al., Cardiovascular morbidity and mortality in ankylosing spondylitis and psoriatic arthritis, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/ j.berh.2019.01.002

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disease, i.e., ankylosing spondylitis (AS), also known as radiographic axial spondyloarthritis (r-axSpA). Similarly, in those with peripheral SpA, the evidence is derived from psoriatic arthritis (PsA). This evidence has been more limited than the other rheumatic diseases and often with conflicting findings. In this review, we examine the available data in PsA and AS concerning CV morbidity and mortality, major CV events, CV risk factors, risk assessment algorithms, and the impact of treatment on CV outcomes.

Cardiovascular mortality Although it is established that CV mortality for RA is elevated compared to the general population [1], the data for PsA are conflicting (Table 1). Jamnitski et al. evaluated mortality in PsA in a systematic review performed in 2013 [3]. Two out of the three included prospective cohort studies [4,5] demonstrated an increased standardized mortality ratio (SMR) of 1.4e1.6 for all-cause mortality. Buckley et al. did not find a significant mortality increase in their prospective PsA cohort from the UK (SMR 0.81 (95% CI 0.57e1.12)), although they did note that CV causes accounted for 38% of deaths [6]. Conversely, in the prospective University of Toronto PsA cohort, Wong et al. found an increased SMR for all-cause mortality and CV death (1.62 [95% CI 1.21e2.12] and 1.33 [95% CI 7.72e21.53], respectively) for PsA compared to that in the general population [4]. In the Jamnitski et al. review, only one out of three population-based studies [7] demonstrated an increased relative risk (RR) for all-cause mortality [3]. In a positive study by Ahlehoff et al. using a Danish national registry, 607 patients with PsA were included among 36,992 patients with psoriasis. Psoriasis was associated with increased rate ratios for all-cause mortality, CV death, and the composite endpoint of myocardial infarction (MI), cerebrovascular accidents (CVA), and CV death, with a high risk seen in those with PsA. The systematic review by Horreau et al. examined CV mortality in PsA across four observational studies and did not find an increase in the Table 1 Cardiovascular mortality in PsA and AS. Citation

PsA Wong 1997 [4] Alhehoff 2010 [7]

Study type

Source

Observational prospective cohort Registry

University of Toronto PsA cohort

Ogdie 2014 [9]

EHR database

Juneblad 2016 [10]

Registry

AS Haroon 2015 [13]

Comparator

General population of Ontario General Psoriasis cohort from Danish population of National Patient Register; Denmark n ¼ 607 with PsA UK THIN primary care database General population of the UK PsA cohort from a county (Skane) in Sweden

General population of Sweden

Administrative/ Databases for provincial health General claims database administrative data in Ontario population of (Ontario Health Insurance Plan Ontario (OHIP) Registered Persons Database; OHIP Claims History Database; Canadian Institute for Health Information Discharge Abstract Database; Ontario Registrar General Death Database)

Outcome collection/ definition

Effect size/result

ICD-9 codes for cardiovascular death ICD-10 codes for cardiovascular death ICD-9 and -10 codes for cardiovascular death ICD-9 codes for cardiovascular death

SMR 1.33 (CI 7.72 e21.53) RR 1.84 (CI 1.11 e3.06) aHR 1.09 (CI 0.91 e1.32)

SMR 1.64 (CI 1.02 e2.52)

HR 1.35 (CI 1.07 ICD-9 CM codes 431, 434, and 436 e1.70) for cardiovascular death

Abbreviations: EHR ¼ electronic health records; SMR ¼ standardized mortality ratio; RR ¼ rate ratio; aHR ¼ adjusted hazard ratio; HR ¼ hazard ratio.

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CV-specific mortality [8]. Two recent studies also had discordant results. Ogdie et al. compared 8,706 patients with PsA and 41,752 patients with RA to 81,573 controls using the UK The Health Improvement Network (THIN) data. The overall and cause-specific mortalities, including the CV mortality, were not increased in PsA compared to those in the general population [9]. Juneblad et al. used Swedish nationwide registries to compare 464 patients with PsA to the general population and found a significantly increased SMR for CVD (1.64 (95% CI, 1.02e2.52)), although the SMR for overall mortality was nonsignificantly elevated [10]. In AS, in an older Finnish prospective cohort study, the overall mortality was 1.5 times than expected for the contemporaneous general population per available registry data [11]. A more recent study by Bakland et al. of a Norwegian AS cohort from a single center reported a significantly increased SMR among men but not women (1.63 [95% CI 1.29 to 1.97] versus 1.38 [0.48 to 2.28], p < 0.001) and that CVD was the most frequent cause of death [12]. Haroon et al. conducted a study of 21,473 patients with AS compared to 86,606 population controls using administrative data from Ontario [13]. The adjusted hazard ratio (HR) of 1.36 (95% CI 1.13e1.65) was significantly elevated for the combined outcome of vascular death. HRs for the individual outcomes of cerebrovascular and CV death were also significantly elevated (1.60 (95% CI 1.17e2.20) and 1.35 (95% CI 1.07e1.70), respectively). Risk factors for vascular death included increasing age, male gender, lower income, dementia, chronic kidney disease (CKD), peripheral vascular disease (PVD), and lack of nonsteroidal anti-inflammatory drug (NSAID) exposure in those over 65 years (in whom prescription medication data were available). Although the data are heterogeneous, CV-related deaths in PsA and AS may be elevated compared to that in the general population. Cardiovascular disease and major adverse cardiac events (MACE) CVD is a category that includes ischemic heart disease (IHD), cerebrovascular disease, PVD, and venous thromboembolism [14]. The American College of Cardiology and American Heart Association (ACC/AHA) use the term atherosclerotic cardiovascular disease (ASCVD) to refer to acute coronary syndromes, angina, coronary revascularization, cerebrovascular disease, and PVD [15]. Finally, the term major adverse cardiac events (MACE) includes acute MI or CVA. In a systematic review by Jamnitski et al., CV morbidity in PsA was increased compared to that in the general population across three cross-sectional studies and one prospective study [3]. A 2017 metaanalysis by Polachek et al. of CV morbidity in patients with PsA included 11 studies; overall, the CV morbidity in PsA was increased by 43% compared to that in the general population [16]. Horreau et al. evaluated MACE in PsA in a systematic review [8]. Both studies assessing MI risk showed that it was increased compared to that in the general population. Only one of the three studies evaluating CVA risk showed that it was increased in PsA. Studies of CVD and MACE in PsA are shown in Table 2. For MI risk in PsA, prospective cohort studies from Toronto by Gladman et al. and from Sweden by Juneblad et al. have found conflicting results [10,17]. By comparing 648 patients with PsA to the general population from the Canadian Community Health Survey, Gladman et al. found a standard prevalence ratio for MI of 2.57 (95% CI 1.73e3.80) [17]. Juneblad et al. found a standardized incidence rate of 0.60 (95% CI 0.40e0.86) for MACE [10]. Both the UK electronic health records (EHR)-based study by Ogdie et al. and the Swedish registry-based study by Bengtsson et al. found that MI was significantly increased in PsA compared to that in the general population [18,19]. Neither prospective cohort study found an elevated risk of CVA in PsA, although Ogdie et al. and Bengtsson et al. did find an elevated CVA risk. Two recently published studies provided conflicting results for MACE as a combined outcome in PsA [20,21]. Lauper et al. studied 1487 patients with axial SpA and 805 patients with PsA from the Swiss national registry. Compared to the RA population, there was no difference in the adjusted incidence rate ratio of combined MACE outcomes for the axial SpA (0.93 (95% CI 0.51e1.69) or PsA cohorts (0.56 (95% CI 0.27e1.14)), suggesting that the risk of MACE in PsA is similar to that in RA [20]. Cooksey et al. did not find a significant difference for combined MACE in a PsA population from a Welsh general practice databank (HR 1.5 (95% CI 0.9e2.5) [21]. A Mayo Clinic inception cohort comprising 86 incident AS cases followed from 1980 to 2009 had a ten-year CVD incidence of 15.8%, which was higher than that expected and underestimated by the Framingham risk score [22]. Although two studies utilizing claims databases found an increased risk of Please cite this article as: Liew JW et al., Cardiovascular morbidity and mortality in ankylosing spondylitis and psoriatic arthritis, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/ j.berh.2019.01.002

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Table 2 Cardiovascular disease and major adverse cardiac events in PsA. Citation IHD Gladman 2009 [17] MI Gladman 2009 [17]

Juneblad 2016 [10] Ogdie 2014 [126]

Study type

Source

Outcome definition

Effect size/result

Observational prospective cohort

University of General population Clinical diagnosis of Toronto PsA cohort of Canada angina based on symptoms

SPR 1.97 (CI 1.24 e3.12)

Observational prospective cohort

University of General population Clinical diagnosis of MI: Toronto PsA cohort of Canada combination of symptoms, cardiac enzyme elevations, and EKG changes Swedish PsA cohort General population ICD-9 codes for MI of Sweden

SPR 2.57 (CI 1.73 e3.80)

Observational prospective cohort EHR database

Bengtsson 2017 Registry [19] CVA Gladman 2009 [17] Juneblad 2016 [10] Ogdie 2014 [9]

Observational prospective cohort Observational prospective cohort EHR database

Bengtsson 2017 Registry [19]

Combined MACE Lauper 2018 Registry [20]

Cooksey 2018 [21]

EHR database

Comparator

UK THIN database

General population READ codes for MI of the UK

Swedish nationwide registries

General population ICD-10 codes for ACS of Sweden

University of General population Clinical diagnosis based Toronto PsA cohort of Canada on neurological examination Swedish PsA cohort General population ICD-9 codes for CVA of Sweden UK THIN database (primary care)

General population READ codes for CVA of the UK

Swedish nationwide registries

General population ICD-10 codes for of Sweden composite stroke (CVA and TIA): I60-61, I6364, and G45

Swiss Clinical Quality Management Registry

Swiss RA population

Welsh Secure Anonymised Information Linkage (SAIL) databank

General population MI, CVA, or CV death of Wales

MI, CVA, or CV death

SIR 0.60 (CI 0.34 e0.99) aHR on DMARDs: 1.36 (CI 1.04e1.72) not on DMARDS: 1.36 (CI 1.01e1.84) aHR 1.76 (CI 1.59 e1.95)

SPR 0.91 (CI 0.34 e2.43) SIR 0.59 (CI 0.32 e0.99) aHR on DMARDS: 1.33 (CI 1.03e1.71) not on DMARDS: 1.13 (CI 0.83e1.55) aHR 1.34 (CI 1.22 e1.48)

Adjusted IRR 0.93 (CI 0.51e1.69) Adjusted prevalence ratio 0.98 (CI 0.58e1.61) HR 1.5 (CI 0.9e2.5)

Abbreviations: EHR ¼ electronic health records; MI ¼ myocardial infarction; ACS ¼ acute coronary syndrome; IHD ¼ ischemic heart disease; CVA ¼ stroke; SPR ¼ standardized prevalence ratios; SIR ¼ standardized incidence ratio; IRR ¼ incidence rate ratio; aHR ¼ adjusted hazard ratio from multivariable analysis; aRR ¼ adjusted relative risk from multivariable analysis.

IHD in AS [23,24], the study by Essers et al. examining the UK Clinical Practice Research Database, a general practice EHR database, did not support an increased IHD risk (adjusted HR 1.20 (95% CI 0.97e1.48)) [25]. Mathieu et al. conducted a systematic review and meta-analysis of 12 longitudinal studies from North America, Europe, and Asia [26] (Table 3). The incidence of MI in AS was 2.6% and was significantly higher than that in the general population (RR 1.44 (95% CI 1.25e1.67)). The CVA incidence in AS was Please cite this article as: Liew JW et al., Cardiovascular morbidity and mortality in ankylosing spondylitis and psoriatic arthritis, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/ j.berh.2019.01.002

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Table 3 Cardiovascular disease and major adverse cardiac events in AS. Citation

Study type

Source

Comparator

Outcome definition Effect size/ Result

IHD Essers 2016 [25]

Primary care EHR database

British Clinical Practice Research Datalink

Szabo 2011 [23]

Claims database

IHD by incomplete aHR 1.20 (CI list provided in the 0.97e1.48) study ICD-9 codes for IHD SPR 1.37 (CI 1.31e1.44)

Szabo 2011 [23]

Claims database

General population of Quebec

Claims database

“Other cardiovascular disease” by ICD-9 codes ICD-9 codes 410 e414 for IHD

SPR 1.36 (CI 1.29e1.44)

Huang 2013 [24]


gie de l'assurance Quebec Re
bec (RAMQ) maladie du Que insurance database (99% of the population)
gie de l'assurance Quebec Re
bec (RAMQ) maladie du Que insurance database (99% of the population) Taiwan Health Insurance database (99% of population)

General population of the UK General population of Quebec

MI Eriksson 2016 [28]

Registry

Swedish nationwide registry

First-ever admission for ACS by ICD-10 code ICD-10 codes for ACS

RR 1.30 (CI 1.0 e1.7)

Bengtsson 2017 Registry [19]

Swedish nationwide registries

Brophy 2012 [29]

EHR database

Essers 2016 [25]

EHR database

Welsh-linked inpatient and outpatient databases; Health Information Research Unit of Swansea University British Clinical Practice Research Datalink

So abstract 2017 [30]

Claims database

Cerebrovascular disease Szabo 2011 Claims [23] database

CVA Bengtsson 2017 Registry [19]

General population of Taiwan, 18e45 years old General population of Sweden General population of Sweden General population of Wales

aHR 1.47 (CI 1.13e1.92)

aHR 1.54 (CI 1.31e1.82)

ICD I21 for MI

aHR 1.28 (CI 0.93e1.74)

General population of the UK General population of British Columbia

AMI; definition unclear from the study ICD-9 or -10 codes for MI

aHR 0.91 (CI 0.65e1.28)


gie de l'assurance Quebec Re
bec (RAMQ) maladie du Que insurance database (99% of the population)

General population of Quebec

ICD-9 codes for cerebrovascular disease

SPR 1.25 (CI 1.15e1.35)

Swedish nationwide registries

General population of Sweden General population of Wales

aHR 1.25 (CI ICD-10 codes for 1.06e1.48) composite stroke (CVA and TIA): I6061, I63-64, and G45 ICD I60-I69 for CVA aHR 1.0 (CI 0.73 e1.39)

British Columbia inpatient and outpatient administrative data

Brophy 2012 [29]

EHR database

Keller 2014 [31]

Claims database

Welsh linked inpatient and outpatient databases; Health Information Research Unit of Swansea University Taiwan Health Insurance database (99% of population)

Lin 2014 [32]

Claims database

Taiwan Health Insurance database (99% of population)

So abstract 2017 [30]

Claims database

British Columbia inpatient and outpatient data

General population of Taiwan General population of Taiwan, 18e45 years old General population of British Columbia

aRR 1.21 (CI 0.98e1.49)

ICD-9 CM codes 430 HR 2.3 (CI 1.9 e438 for CVA e2.8) ICD-9 codes 433 e437 for CVA

RR 1.98 (CI 1.16 e3.20)

ICD-9 or -10 codes for CVA

aRR 1.34 (CI 1.04e1.73)

(continued on next page)

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Table 3 (continued ) Citation

Study type

Combined MACE Lauper 2018 Registry [20]

Source

Comparator

Outcome definition Effect size/ Result

Swiss Clinical Quality Management Registry

Swiss RA population

MI, CVA, or CV death

Adjusted IRR 0.93 (CI 0.51 e1.69) Adjusted prevalence ratio 0.98 (CI 0.58e1.61)

Abbreviations: EHR ¼ electronic health records; MI ¼ myocardial infarction; AMI ¼ acute myocardial infarction; ACS ¼ acute coronary syndrome; IHD ¼ ischemic heart disease; CVA ¼ stroke; SPR ¼ standardized prevalence ratios; IRR ¼ incidence rate ratio; aHR ¼ adjusted hazard ratio from multivariable analysis; aRR ¼ adjusted relative risk from multivariable analysis.

1.9%, which was significantly higher than that in the general population (RR 1.37 (95% CI 1.08e1.73)). MI risk in AS was increased in two registry-based studies from Sweden [19,27] but was not increased in two EHR database studies from the UK [25,28] or a study from British Columbia using provincial administrative and claims data [29]. CVA risk was increased in a Swedish registry-based study, as well as two studies from the Taiwanese claims database and one from British Columbia administrative data [19,29e31]. Only the study from the Welsh EHR database did not find a significant increase in this outcome [28]. The data for MACE in PsA and AS are conflicting and suggest that MI and CVA may be increased compared to those in the general population. Nonischemic cardiac manifestations In addition to CVD, nonischemic cardiac manifestations such as conduction abnormalities, arrhythmias, valvular disease, and diastolic dysfunction are seen in SpA. Aortic involvement in the form of aortic root and ascending aorta inflammation (aortitis), which sometimes leads to valvular insufficiency, is traditionally associated with AS. However, the prevalence of aortic involvement in AS compared to that in the general population is limited to data from small cross-sectional studies applying heterogeneous study methods [32]. Aortic regurgitation was assessed in one prospective study by Bengtsson et al. using the Swedish national registry to compare individuals with AS, PsA, and undifferentiated SpA with controls from the general population [19]. The adjusted HR of aortic regurgitation was 1.9 (95% CI 1.3e2.9) for AS and 1.8 (95% CI 1.4e2.4) for PsA. The authors also found increased incidence of atrial fibrillation, atrioventricular block, and pacemaker dependence in AS and PsA compared to those in the general population. Heslinga et al. performed a systematic review and meta-analysis of 11 studies evaluating diastolic left ventricular dysfunction by echocardiography in AS [33]. Most of the studies were small and cross-sectional. Overall, the studies found that AS was associated with diastolic dysfunction; however, this was defined by the individual metrics on echocardiography with unclear clinical significance, not by the accepted American Society of Echocardiography recommendations of diastology definition [34]; the roles of chronic inflammation on myocardial function and hypertension on left ventricular hypertrophy may underlie changes in diastolic dysfunction when present. Traditional cardiovascular risk factors Traditional CV risk factors in the general population include diabetes mellitus (DM), hypertension, dyslipidemia, tobacco smoking, obesity, and metabolic syndrome. Studies of CV risk factors in PsA and AS are listed in Tables 4 and 5. The data for CV risk factors in PsA come mainly from Canadian prospective cohort studies [35e37], a Norwegian population-based study [38], two UK studies using the THIN EHR database, a large North American registry, Consortium of Rheumatology Researchers of North America (CORRONA) [39], and claims databases from the UK and US [2,40]. The data for AS come Please cite this article as: Liew JW et al., Cardiovascular morbidity and mortality in ankylosing spondylitis and psoriatic arthritis, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/ j.berh.2019.01.002

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Table 4 Cardiovascular risk factors in PsA. Citation

Study type

Source

Comparator

Prospective cohort Prospective cohort Population-based study Jafri 2017 [40] Registry Dubreuil 2014 [48] Registry Labitigan 2014 [39] Registry, crosssectional analysis Dreiher 2013 [46] Claims database

University of Toronto PsA cohort University of Toronto PsA cohort Norway e Nord Trondelag Health Study 3 (HUNT) UK THIN primary care database UK THIN primary care database CORRONA registry

Psoriasis OR 2.03 (CI 0.85e4.81) General population SPR 1.43 (CI 1.2e1.7) General population p ¼ 0.16

IsraeleClalit database

Solomon 2009 [49] Claims database

British Columbia insurance claims database US Medicare insurance claims database

General population females: OR 1.60 (CI 1.02e2.52) males: OR 0.71 (CI 0.42 e1.22) General population aHR 1.4 (CI 1.3e1.5)

Diabetes Husted 2011 [35] Eder 2017 [37] Gulati 2016 [38]

Radner 2017 [47] Hypertension Husted 2011 [35] Gulati 2016 [38] Jafri 2017 [40]

Claims database

Prospective cohort Population-based study Registry

Labitigan 2014 [39] Registry, crosssectional analysis Radner 2017 [47] Claims database Dyslipidemia Husted 2011 [35] Jafri 2017 [40]

Prospective cohort Registry

Labitigan 2014 [39] Registry, crosssectional analysis Radner2017 [47] Claims database Obesity Husted 2011 [35] Eder 2017 [36] Gulati 2016 [38]

Prospective cohort Caseecontrol study Population-based study Labitigan 2014 [39] Registry, crosssectional analysis Radner 2017 [47] Claims database Metabolic syndrome Labitigan 2014 [39] Registry, crosssectional analysis Mok 2011 [59] Cross-sectional study Tobacco use Gulati 2016 [38] Population-based study Labitigan 2014 [39] Registry, crosssectional analysis

University of Toronto PsA cohort NorwayeNord Trondelag Health Study 3 (HUNT) UK THIN primary care database

CORRONA registry

Effect size/Result

General population aOR 1.38 (CI 1.31e4.50) General population aHR 1.33 (CI 1.09e1.61) RA aOR 1.44 (CI 1.07e2.28)

General population IRR 1.14 (CI 1.03e1.26)

Psoriasis aOR 2.17 (CI 1.22e3.83) General population aOR 2.17 (CI 1.23e3.83) General population Prevalence: aOR 1.31 (CI 1.26e1.37) Incidence: aHR 1.31 (CI 1.23e1.39) RA aOR 1.09 (CI 0.81e1.47)

US Medicare insurance claims database

General population IRR 1.17 (CI 1.11e1.24)

University of Toronto PsA cohort UK THIN primary care database

Psoriasis aOR 0.76 (CI 0.38e1.51) General population Prevalence: aOR 1.23 (CI 1.18e1.29) Incidence: aHR 1.24 (CI 1.16e1.34) RA aOR 1.51 (CI 1.15e1.98)

CORRONA registry US Medicare insurance claims database

General population IRR 1.10 (CI 1.04e1.17)

University of Toronto PsA cohort University of Toronto PsA cohort NorwayeNord Trondelag Health Study 3 (HUNT) CORRONA registry

Psoriasis aOR 1.29 (CI 0.82e2.04) Psoriasis aOR 1.77 (CI 1.23e2.56) General population p < 0.0001

US Medicare insurance claims database

General population IRR 1.25 (CI 1.14e1.36)

CORRONA registry

RA

RA

aOR 1.19 (CI 0.90e1.57)

aOR 1.44 (CI 1.05e1.96)

Hong Kong single-center outpatient General population aOR 2.69 (CI 1.60e4.50) cohort NorwayeNord Trondelag Health Study 3 (HUNT) CORRONA registry

General population p ¼ 0.02 General population p ¼ 0.02

Abbreviations: EHR ¼ electronic health records; IRR ¼ incidence rate ratio; aHR ¼ adjusted hazard ratio; aOR ¼ adjusted odds ratio.

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Table 5 Cardiovascular risk factors in AS. Citation Diabetes Bremander 2011 [42] Brophy 2012 [29]

Study type

Source

Comparator

Effect size/result

Registry

Skane Health Care Register e Sweden

EHR database

Welsh linked inpatient and outpatient database; Health Information Research Unit of Swansea University Ontario administrative databases

General population General population

Overall SMR 1.41 (CI 1.10e1.78) aOR 1.27 (CI 1.09 e1.49)

Haroon 2015 [13] Chou 2014 [43]

Administrative/claims database Claims database

Chen 2014 [44]

Claims database

Hypertension Bremander 2011 [42] Brophy 2012 [29] Haroon 2015 [13] Chou 2014 [43] Dyslipidemia Bremander 2011 [42] Brophy 2012 [29]

Registry

Skane Health Care Register e Sweden

EHR database

Welsh-linked inpatient and outpatient database; Health Information Research Unit of Swansea University Ontario database

General population General population

Administrative/claims database Claims database

General population Taiwan Health Insurance database (99% General of population) population

Registry

Skane Health Care Register e Sweden

EHR database

Welsh-linked inpatient and outpatient database; Health Information Research Unit of Swansea University Taiwan Health Insurance database (99% General of population) population

Chou 2014 [43]

Claims database

Obesity Lopez-Medina 2017 [45]

Cross-sectional

Metabolic syndrome Mok 2011 [60] Cross-sectional Tobacco use Lopez-Medina 2017 [45]

General population Taiwan Health Insurance database (99% General of population) population Taiwan Health Insurance database (99% General of population) population

Cross-sectional

General population General population

p ¼ 0.07 p < 0.009 HR 1.16 (CI 1.05 e1.09) Overall SMR: 1.98 (CI 1.72e2.28) aOR 1.65 (CI 1.47 e1.85) p ¼ 0.14 p < 0.0001

Overall SMR 1.26 (CI 0.89e1.72) aOR 1.12 (CI 0.95 e1.33) p < 0.0001

COMOSPA cohort e multi-national study; subset from North Europe and Mediterranean. n ¼ ~2000

none

Prevalence: 23.4%

Hong Kong single-center cohort

General population

OR 0.59 (CI 0.30 e1.15)

COMOSPA cohort e multinational study; subset from North Europe and Mediterranean. n ¼ ~2000

none

Prevalence: 31.2%

Abbreviations: EHR ¼ electronic health records; SMR ¼ standardized mortality ratio; aOR ¼ adjusted odds ratio; HR ¼ hazard ratio.

mainly from the Swedish nationwide registry [41], a Welsh EHR database [28], and the Taiwan Health Insurance claims database [42,43]. CV comorbidities have also been assessed broadly in SpA using the large, international cross-sectional COMOrbidities in SPondyloArthritis (COMOSPA) cohort [44]. The data of prevalence and incidence derived from these sources are limited, as cohort studies usually include patients with more severe disease, and the validity of administrative and EHR data may be lacking. Diabetes mellitus DM is considered a CVD risk equivalent [15,45]. The prevalence of DM in PsA ranges from 5.3% to 16.6% [35,37e40,46,47], with an incidence of 7.3e14.7/1000 person-years, which is significantly increased compared to the general population [37,40,46e49] as well as to the RA population in the CORRONA registry [39]. The prevalence of DM in AS ranges from 7.3% to 13.5% and is significantly increased compared to the general population [28,41e43]. Please cite this article as: Liew JW et al., Cardiovascular morbidity and mortality in ankylosing spondylitis and psoriatic arthritis, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/ j.berh.2019.01.002

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Hypertension In the general population, hypertension is an independent risk factor for CVD. For every 20 mmHg increase in systolic blood pressure above 115 mmHg and every 10 mmHg increase in diastolic blood pressure above 75 mmHg, the risk of MACE is doubled [50,51]. The prevalence of hypertension in PsA ranges from 19.9% to 45.3% [35,38e40,46,47], with an incidence of 27.3e79.8/1000 person-years, which is significantly increased compared to the general population [35,38,40,47,48]. The prevalence of hypertension in AS ranges from 11% to 43.6% and is significantly increased compared to the general population [28,41e43]. Dyslipidemia Dyslipidemia refers to elevated serum levels of low-density lipoprotein (LDL)echolesterol and triglyceride and decreased levels of high-density lipoprotein (HDL)echolesterol. Primary and secondary prevention trials with lipid-lowering agents have shown a 40 mg/dL (1.0 mmol/L) reduction in LDL corresponding to a 20e25% risk reduction in CV mortality and nonfatal MI [15]. The overall prevalence of dyslipidemia in PsA ranges from 11.6% to 61.6% [35,37,40,46,47,52e54], with an incidence of 11.0e52.0/1000 person-years, and several studies indicate these prevalence ranges and incidence rates are significantly higher than those in the general population [40,47,48,52,54]. The prevalence of dyslipidemia in AS ranges from 2.9% to 15.8% and is significantly increased compared to the general population in a Taiwanese study [42] but not in a Swedish study [41]. Obesity Being overweight or obese is associated with an increased risk of CV death and all-cause mortality. Obesity may be measured by body mass index (BMI) or other factors such as the waist circumference or waist-to-height ratio [14]. The overall prevalence of obesity in PsA ranges from 6.0% to 45% [2,35,36,38,39,44] and was significantly higher than that in the general population in two studies [36,38]. The incidence of obesity in PsA was 32.9 per 1000 person years (incidence rate ratio [IRR] 1.25 (95% CI 1.14e2.56)) from the US Medicare data [47]. A prospective study of the US Nurses Health cohort showed that obesity was associated with the incident development of PsA in patients with psoriasis, with the HR increasing with increasing BMI [55]. Compared to psoriasis, there was a significantly increased OR for prevalent obesity in PsA in the University of Toronto cohort [35]. In a Canadian caseecontrol study comparing early PsA to psoriasis patients, obesity was more frequent in PsA, with an OR 1.77 (95% CI 1.23e2.56), and high BMI was associated with older age at PsA onset. The analysis also found a significant interaction between HLAB27 status and obesity, suggesting a possible differential effect on obesity and PsA risk that was dependent on genetic factors [36]. Obesity was also associated with worse response to TNFi in Danish and Icelandic PsA registries of a combined 1271 patients [56]. Metabolic syndrome The metabolic syndrome is a cluster of interrelated traditional CV risk factors that predict the development of DM and CVD. The diagnostic criteria, per the joint recommendations proposed in 2009, are BP  130/85 mmHg or treatment for hypertension, serum triglyceride 150 mg/dL (1.7 mmol/L) or treatment for hypertriglyceridemia, HDL 40 mg/dL (1.0 mmol/L) in men and <50 mg/dL (1.2 mmol/L) in women, fasting plasma glucose 100 mg/dL (5.5 mmol/L) or treatment for DM, and increased waist circumference per criteria that are dependent on ethnicity and gender [57]. The overall prevalence of metabolic syndrome in PsA ranges from 27% to 59.3% [39,58] and was significantly higher than those in an RA population [39]. In a Hong Kong cross-sectional study by Mok et al., the prevalence of metabolic syndrome in PsA was 38%, compared to that of 11% in AS and 20% in RA. The multivariable model showed that only PsA, and not AS or RA, had significantly increased metabolic syndrome prevalence compared to the general population (OR 2.69 (95% CI 1.60e4.50)) [59]. Please cite this article as: Liew JW et al., Cardiovascular morbidity and mortality in ankylosing spondylitis and psoriatic arthritis, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/ j.berh.2019.01.002

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A study of Irish patients with PsA found that metabolic syndrome was associated with severe PsA and smoking history in a multiple regression analysis [60], while two Italian studies showed that the metabolic syndrome was associated with skin psoriasis severity, a higher BMI, and smoking in multivariable analyses, as well as a lower likelihood of achieving minimal disease activity in those on TNFi over a 24 month follow-up [58,61].

Tobacco smoking In European studies, current tobacco smoking is associated with a doubled 10-year fatal CVD risk [14]. In the US, 30% of CV mortality is attributable to smoking [62]. Gulati et al. found a 21.3% prevalence of tobacco smoking compared to 16.4% in the general Norwegian population, which reached statistical significance (p ¼ 0.02) [38]. In the study by Labitigan et al., the prevalence of tobacco smoking was significantly lower than that in the RA cohort in CORRONA (9% vs. 14%, p ¼ 0.02) [39]. There was a 31.2% overall smoking prevalence in SpA from the COMOSPA cohort when evaluating patients drawn from North Europe and the Mediterranean [44]. In the Danish DANBIO registry of patients with AS and PsA, current and former smoking were shown to be associated with short TNFi treatment adherence and poor response [63,64]. The available data suggest that individual CV risk factors are elevated in PsA and AS, which may partially explain the elevated MACE seen in these populations. Cardiovascular risk algorithms In the guidelines issued jointly by ACC and AHA, and as well as in the recommendations from the European Society of Cardiology (ESC), the use of multivariable CV risk algorithms to predict CV risk is advised. On the basis of this risk score, individuals are sorted into categories for primary and secondary CVD prevention. The 2013 ACC/AHA guidelines for the management of dyslipidemia support the use of the newly developed Pooled Cohort Equation, which was developed using data from multiple large US cohorts to predict the ten-year ASCVD risk in individuals 21e79 years old [15]. The 2016 ESC recommendations for CVD prevention support the use of the Systemic Coronary Risk Evaluation (SCORE) model, developed specifically for a European population, which predicts the ten-year risk of fatal CV events for those 40e65 years old [14,65]. Both the Pooled Cohort Equation and the SCORE model are considered improvements upon the Framingham risk score, which underestimates risk in women and younger patients and overestimates risk in some European populations [65,66]. In a SpA population, CV risk may be underestimated by these algorithms. The actual ten-year ASCVD risk was nearly double than that estimated by the Framingham model in a population-based PsA cohort from Olmsted County [67]. In one Scandinavian study of patients with PsA, the SCORE estimated ten-year risk was similar to age- and sex-matched controls despite an increased baseline prevalence of CV risk factors [38]. In another Scandinavian study, AS but not PsA patients had a lower ten-year risk per SCORE model than patients with RA [68]. Shen et al. evaluated 146 patients with PsA with a mean age of 49.4 years, of whom 61.6% were male. Risk scores were assessed using several models including SCORE, the Pooled Cohort Equation, and the Framingham risk score. A multiplier modification of 1.5 advocated by the EULAR guidelines for inflammatory rheumatic diseases was also applied. The sensitivity of all risk scores for subclinical atherosclerosis as evaluated by carotid ultrasound remained low, even after adjustment by the EULAR multiplier modification for inflammatory rheumatic disease [69]. These studies demonstrate that CV risk is underestimated in those with PsA and AS even when using guideline recommended risk scores. This suggests that the presence of nontraditional CV risk factors increases the overall CV risk in such populations. Subclinical atherosclerosis Endothelial dysfunction, changes in plaque composition increasing the vulnerability to rupture, and a pro-thrombotic state all contribute to the increased atherosclerotic burden in PsA and AS, like in RA Please cite this article as: Liew JW et al., Cardiovascular morbidity and mortality in ankylosing spondylitis and psoriatic arthritis, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/ j.berh.2019.01.002

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[70]. Inflammatory cytokines such as TNF, IL-6, and IL-17 are implicated in the pathogenesis of endothelial dysfunction and atherogenesis [71]. Plaque burden The presence of carotid plaque can be considered a surrogate for atherosclerotic disease. Carotid plaque was found on ultrasound in 39% of patients with PsA in one study [72]. This cohort, however, had a high baseline prevalence of traditional CV risk factors. In a cohort of patients with AS without clinical CVD, the prevalence of carotid plaques was 29.7% [73]. Szentpetery et al. demonstrated a prevalence of 76% for coronary plaque in PsA compared to 44% for controls, as assessed by coronary computer tomography angiography in a small study [74]. Disease activity and severity were more predictive of plaque burden than traditional risk factors. Carotid intima-media thickness The carotid intima-media thickness (CIMT) is a noninvasive measurement using carotid ultrasound. Increased CIMT is an independent predictor of MI and CVA, although data are limited for younger populations than for older populations [75]. AS was associated with significantly increased CIMT based on the meta-analysis by Mathieu et al. of six studies, including the seminal study by Gonzalez-Juanatey et al. [73,76]. A more recent prospective study of 60 patients with AS had concordant findings, and in a linear regression model, increased CIMT was positively correlated with age at AS onset, disease activity, functional scores, and inflammatory markers [77]. Arterial stiffness The carotid-femoral pulse wave velocity (PWV) is a noninvasive method to measure arterial stiffness and is a strong predictor of future CV events, CV mortality, and all-cause mortality [78,79]. The augmentation index is another method for estimating arterial stiffness. It is unclear whether abnormal arterial stiffness is more prevalent in the AS population than in the general population; two prospective studies in AS had conflicting results [80,81]. The aortic PWV was significantly higher in patients with PsA than in controls and was associated with disease duration in one study [82]. Similarly, Shang et al. found that there was significantly increased ventricular and arterial stiffness for PsA compared to controls and was associated with disease duration greater than ten years in a multivariable analysis [83]. Endothelial dysfunction Endothelial dysfunction is implicated in CV risk factors such as DM and hypertension, as well as in chronic inflammatory diseases [71]. Inflammation leads to alterations in coagulation, increased vasoconstriction and impaired vasodilatation, and the formation of reactive oxygen species. Impaired flow-mediated dilation (FMD), a measure for endothelial dysfunction using the brachial artery diameter, is associated with increased CV risk in the general population, with a stronger relationship in those with underlying chronic disease [84]. Sari et al. demonstrated impaired endothelial function by FMD in patients with AS compared to controls [85]. Similar findings were seen in two PsA studies [86,87]. Lipid profile Systemic inflammation is thought to alter lipid structure and function to create a pro-atherogenic profile [88]. In RA, the inflammatory state decreases total cholesterol (TC), LDL, and HDL, while antiinflammatory therapy increases these levels. This lipid paradox has been shown in cross-sectional studies in AS and PsA, although causal data are lacking [81,89,90]. Please cite this article as: Liew JW et al., Cardiovascular morbidity and mortality in ankylosing spondylitis and psoriatic arthritis, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/ j.berh.2019.01.002

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Other biomarkers Hyperuricemia is associated with increased CV risk. In a small cross-sectional study of patients with PsA, elevated serum uric acid was associated with increased CIMT on ultrasound, suggesting that this association may hold for PsA as well, although larger and prospective studies are currently lacking [91]. Subclinical atherosclerosis is common in PsA and AS. The role of inflammation, especially on endothelial function and lipid profiles, needs to be further elucidated. Anti-inflammatory treatment outcomes In addition to traditional CV risk factors and the underlying inflammation due to the disease itself, the pharmacological treatments for AS and PsA may have an impact on the CVD burden. NSAIDs The anti-inflammatory effects of NSAIDs are mediated through COX-2 inhibition. Selective COX-2 inhibition shifts the balance toward thromboxane-induced vasoconstriction and platelet activation; this is thought to be the mechanism underlying blood pressure elevation, and an increase in CV events seen in COX-2-specific inhibitors (“coxibs”) such as rofecoxib [92]. The degree of COX-2 selectivity is also hypothesized to underlie differential CV effects among traditional nonselective NSAIDs. A 2011 network meta-analysis by Trelle et al. of randomized controlled trials (RCTs) comparing NSAIDs to nonNSAIDs or to placebo in the general population showed that rofecoxib was associated with the highest MI risk, ibuprofen with the highest CVA risk, and etoricoxib and diclofenac with the highest risk of CV death [93]. The Coxib and Traditional NSAID Trialists' Collaboration performed a meta-analysis in 2013 of RCTs comparing NSAIDs with placebo and NSAIDs with other NSAIDs and found that major CV events (MI, CVA, or CV death) were significantly increased in coxibs and diclofenac but not in ibuprofen or naproxen [92]. However, there was an increased adjusted rate ratio for MI or CV death in ibuprofen, which was not seen in naproxen. More recently, the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION) trial demonstrated the noninferiority of celecoxib to naproxen and ibuprofen with regard to the composite of CV death, MI, or CVA in individuals with OA or RA with elevated CV risk [94]. However, the PRECISION trial is limited by low adherence and retention rates and the low dosing of celecoxib utilized in the study. The effect of NSAIDs on CV risk may be different in those with inflammatory rheumatic diseases, as suggested by two population-based studies in RA that showed significantly decreased MACE and CV death with NSAID use [95,96]. Using the Taiwan National Health Insurance data, Tsai et al. assessed the effect of NSAID use on MACE risk at 12 months in newly diagnosed AS [97]. A significantly decreased MACE risk was associated with an NSAID medication possession rate >80% and a longer duration of NSAID use. In a separate Taiwanese caseecontrol study, AS patients taking celecoxib were found to have a negative association with CAD events compared to AS patients not taking celecoxib (OR 0.34 (95% CI 0.13e0.89)) [98]. In a study using the Swedish national patient registry, patients with AS unexposed to NSAIDs had more baseline comorbidities and an increased risk of congestive heart failure, although these findings may be limited by confounding by indication as those with a high risk of heart failure would be less likely to be treated with NSAIDs [99]. Secondary outcomes from other populationlevel studies also suggest a possibly cardioprotective effect of long-term NSAID use for those with AS or PsA; however, the validity of these results is questionable [10,13]. In the most recent study on NSAID use on CV outcomes in AS, Dubreuil, et al. performed a nested case-control study comparing MI events in a SpA cohort to an OA cohort using the UK THIN database [100]. Current diclofenac use was associated with increased MI risk in SpA (adjusted OR 3.32 (95% CI 1.57e7.03), as well as in OA, but the risk differed between the two groups (ratio of adjusted OR with OA as the referent, 2.64 (95% CI 1.24e5.58). Additionally, the authors found that current naproxen use was not associated with increased MI risk in SpA (adjusted OR 1.19 (95% CI 0.53e2.68). These findings hearken back to the differential effects on CV outcomes engendered by different NSAIDs. There are no studies specifically addressing NSAID use on CV risk in a PsA population. Please cite this article as: Liew JW et al., Cardiovascular morbidity and mortality in ankylosing spondylitis and psoriatic arthritis, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/ j.berh.2019.01.002

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Corticosteroids Excess exogenous corticosteroids increase CV risk through pleiotropic effects that are often dependent on cumulative dosage and duration [101]. In a meta-analysis by Roubille et al., corticosteroids increased the risk of all MACE in RA, although this may be related to confounding by indication [102]. The direct data for this relationship in PsA and AS are sparse. Conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) Although csDMARDs lack efficacy in SpA, there are some data on CV outcomes with methotrexate (MTX) and sulfasalazine (SSZ) in PsA. In a Taiwanese study of psoriatic patients with or without PsA, stratified by MTX use, there was no significant difference in the multivariable analysis for IHD hospitalization between the MTX and control cohorts [103]. These data should be interpreted with caution, as at baseline, only 3.3% of the control group had PsA, while 15.2% of the patients in the PsA cohort were on MTX. In another Taiwanese study, Wu et al. studied the association between SSZ usage and CAD in newly diagnosed patients with AS [98]. After adjustment for age, gender, and CV comorbidities, those using SSZ had a negative association with CAD events compared to those not using sulfasalazine (OR 0.63 (95% CI 0.40e0.99)). The CV data of the Janus kinase inhibitor tofacitinib in PsA are limited to postmarketing adverse events. TNF inhibitors In RA, the use of TNFi was associated with a decrease in all MACE (RR 0.70, CI 0.54e0.90) in a metaanalysis by Roubille et al. [102]. There are limited data for the effect of TNFi use on MACE in PsA or AS, although studies do demonstrate effects on parameters such as the lipid profile and subclinical atherosclerosis. In a small prospective study, Spanakis et al. found a sustained increase in HDL, in patients with AS and PsA exposed to infliximab for six months [104]. In two larger prospective observational studies of patients with AS and PsA treated with etanercept, the lipid profile was overall improved upon follow-up up to five years [105,106]. These studies suggest a normalization of lipid levels with anti-inflammatory treatment. Two small prospective observational studies on subjects with PsA and AS on TNFi treatment found that there was significantly decreased CIMT on two-year followup, although CIMT was significantly higher in those who discontinued TNFi [107,108]. In a small prospective study of patients with AS and PsA, those on TNFi after one year had improved aortic PWV and decreased CIMT progression [109]. However, two other studies that followed up patients with AS on TNFi for 24 weeks to 12 months did not show a significant change in the arterial stiffness [80,110]. In a small study, van Eijk et al. found that the microvascular function was impaired in patients with AS compared to controls but improved following treatment with etanercept, suggesting that TNFi treatment may improve endothelial dysfunction in AS [111]. We do not yet have data on the CV effects of other biologics such as the IL-17A or IL-12/23 inhibitors used in the treatment of SpA. Management of cardiovascular disease and risk factors The 2015/2016 EULAR recommendations for the management of CVD in inflammatory rheumatic diseases recommend the use of risk prediction algorithms such as SCORE to help determine which individuals require lipid-lowering and antihypertensive treatment. For RA, they recommend a multiplication factor of 1.5. They do not make the same recommendation for PsA or AS, as the available evidence in these diseases is still more scarce and less robust to allow for a better estimation of the adjustment needed in the SCORE. The use of the TC/HDL ratio to determine the lipid profile is also encouraged. The authors do not make specific recommendations on screening, lifestyle modifications, or treatment of hypertension and dyslipidemia compared to the recommendations that apply to the general population [2]. The 2016 ESC recommendations for CVD prevention specifically address those Please cite this article as: Liew JW et al., Cardiovascular morbidity and mortality in ankylosing spondylitis and psoriatic arthritis, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/ j.berh.2019.01.002

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with autoimmune diseases and also recommend the 1.5 multiplier for those with RA on the basis of class IIa, level B evidence [45]. There are no specific recommendations for this population in the ACC/ AHA guidelines. Despite these recommendations, those with PsA or AS who have concomitant hypertension or dyslipidemia are underscreened and undertreated. In the COMOSPA cohort, a complete CV evaluation of blood pressure, glycemic control, and cholesterol levels had only been undertaken in 50.5% of patients with SpA in the previous year per chart review [112]. Blood pressure screening occurred in 81%, but only 56% had had lipid evaluation. In a Dutch study of 254 patients with AS, although 37% had an indication for CV risk treatment, they were being undertreated in terms of CV risk prevention [113]. In one multinational study, underdiagnosis and undertreatment were found to be associated with being young and male [114]. Fig. 1 shows the traditional CV risk factors that pertain to CVD burden and MACE risk in AS and PsA and their diagnostic criteria. Dyslipidemia and lipid-lowering therapy The 2013 ACC/AHA guidelines recommend high intensity statin therapy with atorvastatin or rosuvastatin to those younger than 75 years with clinical ASCVD and those older than 21 years with LDL 190 mg/dL (4.9 mmol/L). Moderate- or high-intensity statin therapy is recommended for those with clinical ASCVD >75 years, those with DM 40e75 years old (LDL 70e189 mg/dL (1.8e4.8 mmol/L)), and those without DM 40e75 years old (LDL 70e189 mg/dL (1.8e4.8 mmol/L)) and a ten-year ASCVD risk of 7.5% per the Pooled Cohort Equation [15]. The 2016 ESC recommendations advise risk calculation using SCORE to categorize patients into risk categories, with treatment targets for LDL based on these categories (i.e., 70 mg/dL (1.8 mmol/L) for the very high-risk group and 100 mg/dL (2.6 mmol/L) for the high-risk group) [45]. Both sets of recommendations acknowledge the potential adverse events related to the initiation of statin therapy: myopathy in 10e15%; rhabdomyolysis as a rare occurrence, at 1e3 per 100,000 person-years; hepatic dysfunction in 0.5e2.0%; and multiple drugedrug interactions [15,45].

Fig. 1. Cardiovascular disease and major adverse cardiac events, and their traditional risk factors. Abbreviations; ACC/AHA: American College of Cardiology/American Heart Association; ASCVD: Atherosclerotic cardiovascular disease; BMI: body mass index; ESC: European Society of Cardiology; HDL: high-density lipoprotein; LDL: low density lipoprotein; SBP: systolic blood pressure; WHO: World Health Organization.

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Semb et al. performed a post-hoc analysis of two RCTs assessing atorvastatin therapy as secondary ASCVD prevention [115]. These two trials included a total of 35 individuals with PsA, 46 with AS, and 199 with RA. Statin initiation was associated with 20% reduction in overall CVD risk in those with inflammatory joint disease, which is similar to findings in the general population. Interestingly, the authors also found a significant protective effect against CVD seen in AS (HR 0.26, 95% CI 0.07e0.91) but not greater than patients without inflammatory rheumatic diseases. Several other trials have evaluated the effects of statin therapy in patients with AS, with beneficial outcomes on the lipid profile, arterial wall inflammation, and endothelial function [116e120]. In a UK cohort study using propensity score matching, statin initiation in patients with AS was associated with a 37% reduction in all-cause mortality risk compared to those not initiated on statins [121]. Hypertension and blood pressure control The 2013 ESC recommendations define hypertension as a blood pressure 140/90 mmHg. The recommended treatment target is < 140/90 mmHg for the general population, inclusive of those with clinical ASCVD, DM, and CKD, although the elderly may be treated with more lenient targets. Lifestyle modifications and regular physical activity are generally recommended in addition to pharmacological therapy [50]. Until recently, the prevailing hypertension guidelines in the US were those from the Joint National Committee 8, in which the recommended blood pressure goal was <140/90 mmHg for individuals 30e59 years old, including those with DM and CKD, and <150/90 mmHg for individuals 60 years old [122]. In 2017, the ACC/AHA released new guidelines in which hypertension was redefined as a blood pressure >130/80 mmHg, with treatment goals for <130/80 mmHg in the majority of populations, including those with stable IHD, heart failure, CKD, and DM [51]. There are no specific studies evaluating outcomes of blood pressure control in AS or PsA. Diabetes The World Health Organization (WHO)'s diagnostic criteria for DM are one or more of the following: fasting blood glucose 126 mm/dl (7.0 mmol/l), 2 -hour oral glucose tolerance test 200 mg/dl (11.1 mmol/l), and hemoglobin A1c  6.5% (48 mmol/mol) [123]. The 2018 ACR/National Psoriasis Foundation (NPF) guideline for the treatment of PsA advise keeping an individual's diagnosis of diabetes in mind when choosing medications, particularly as those with diabetes are at increased risk of hepatotoxicity with MTX [124]. Obesity and the metabolic syndrome Overweight is defined as a BMI of 25.0e29.9 kg/m2, while obese is any BMI 30 kg/m2 [125]. For individuals with PsA who are overweight or obese, the ACR/NPF recommend weight loss [124]. The 2015 Group for Research and Assessment of Psoriasis and PsA (GRAPPA) recommendation also support achieving and maintaining a healthy weight in all patients [126]. Di Minno et al. performed two prospective studies in patients with PsA on TNFi, which showed that obesity was associated with a poorer probability of achieving or maintaining minimal disease activity, while 5% body weight loss in obese or overweight individuals predicts treatment response [58,61,127,128]. Disease control The EULAR recommendations for CVD management in inflammatory rheumatic diseases recommend the optimization of disease activity and advise caution for the use of NSAIDs and corticosteroids, particularly for RA [2]. However, these recommendations for cautious NSAID use may not apply in AS because corticosteroids are not commonly used, as they do not have a demonstrated efficacy, NSAIDs remain the first-line therapy for the disease, the population is diagnosed at a younger age and possibly because data suggesting a potential cardioprotective effect with long-term NSAID use. The data are currently too limited to make more precise recommendations. Please cite this article as: Liew JW et al., Cardiovascular morbidity and mortality in ankylosing spondylitis and psoriatic arthritis, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/ j.berh.2019.01.002

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Summary Evidence is mounting for an increased CVD burden in AS and PsA as compared to the general population. This elevated risk is only partially attributable to traditional risk factors such as comorbid hypertension, dyslipidemia, DM, obesity, and the metabolic syndrome, even though the prevalence of these disorders is also increased in this population. Chronic, systemic inflammation likely contributes to the development of accelerated atherosclerosis, which can be measured by several noninvasive techniques. Further research into the effects of anti-inflammatory therapy, especially of NSAIDs and biologics, including TNFi, on the CV burden is needed. Recommendations for management must first highlight the increased CV risk in AS and PsA, as risk factors remain underdiagnosed and undertreated. We can then begin to determine how these risk factors can best be intervened upon in such individuals.

Practice points  Patients with AS and psoriatic arthritis (PsA) have an increased prevalence of traditional CV risk factors such as hypertension, dyslipidemia, DM, obesity, and metabolic syndrome.  The traditional CV risk factors alone do not wholly account for the increased CV burden in these diseases, as evidenced by underestimation using risk algorithms derived from the general population.  Noninvasive measures such as carotid ultrasonography and measurement of arterial stiffness and endothelial dysfunction using PWV and FMD, respectively, demonstrate subclinical atherosclerosis in AS and PsA.  It is unclear whether treatment with NSAIDs increases CV risk or provides a net cardioprotective benefit in AS.  Treatment with TNF inhibitors, while actively controlling inflammation, may provide a cardioprotective benefit.  Comorbid CV risk factors are under-recognized and appear to be undertreated in AS and PsA despite available guidelines.

Research agenda  Prospective studies on CV risk factors in SpA are needed.  The utility of noninvasive measurements of subclinical atherosclerosis and endothelial dysfunction needs to be assessed, and the optimal CVD screening modality ought to be determined.  The effect of NSAIDs and biologic DMARDs on CV risk factors and disease needs to be further elucidated.

Funding Dr. Liew receives support through the University of Washington T32 training grant and the ASAS international society. Dr. Gensler is supported by the Spondylitis Association of America and the Russel Engelman Rheumatology Research Center at the University of California, San Francisco. Dr Ramiro receives no funding. Conflicts of interest Dr. Liew has nothing to disclose. Dr. Gensler receives research support from Amgen, AbbVie, Novartis, Pfizer, and UCB and has been a consultant for AbbVie, Galapagos, Janssen, Novartis, and Eli Please cite this article as: Liew JW et al., Cardiovascular morbidity and mortality in ankylosing spondylitis and psoriatic arthritis, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/ j.berh.2019.01.002

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Lilly. Dr. Ramiro receives grant support from MSD and has been a consultant for AbbVie, Eli Lilly, MSD, Novartis, and Pfizer.

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Please cite this article as: Liew JW et al., Cardiovascular morbidity and mortality in ankylosing spondylitis and psoriatic arthritis, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/ j.berh.2019.01.002