ARD Online First, published on February 20, 2017 as 10.
1136/annrheumdis-2016-210275
Handling editor Tore K Kvien
▸ Additional material is
published online only. To view
please visit the journal online
(http://dx.doi.org/10.1136/
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1
Division of Epidemiology,
University of Toronto Dalla
Lana School of Public Health,
Toronto, Ontario, Canada
2
Rouge Valley Health System,
Toronto, Ontario, Canada
3 incident MI and five major types of arthritis: rheumatoid
Department of Family and
Community Medicine, Institute
for Clinical Evaluative Sciences,
Centre for Research on Inner
City Health, Li Ka Shing
Knowledge Institute,
St. Michael’s Hospital,
University of Toronto, Toronto,
Ontario, Canada
4
Institute for Work and Health,
Toronto, Ontario, Canada
5
Division of Health Care &
Outcomes Research, Toronto
Western Research Institute,
Toronto, Ontario, Canada
Correspondence to
Elizabeth M Badley, Toronto
Western Research Institute,
399 Bathurst Street, MP-10th
Floor, Suite 310, Toronto,
Canada M5T 2S8; e.badley@
utoronto.ca
Received 27 July 2016
Revised 16 January 2017
Accepted 22 January 2017
To cite: Schieir O,
Tosevski C, Glazier RH, et al.
Ann Rheum Dis Published
Online First: [ please include
Day Month Year]
doi:10.1136/annrheumdis-
2016-210275
Copyright Article author (or their employer) 2017. Produced by BMJ Publishing Group Ltd (& EULAR) under licence.
Clinical and epidemiological research
EXTENDED REPORT
Incident myocardial infarction associated with major
types of arthritis in the general population:
a systematic review and meta-analysis
Orit Schieir,1 Cedomir Tosevski,2 Richard H Glazier,3 Sheilah Hogg-Johnson,4
Elizabeth M Badley1,5
ABSTRACT
Objective To synthesise, quantify and compare risks
for incident myocardial infarction (MI) across five major
types of arthritis in population-based studies.
Methods A systematic search was performed in
MEDLINE, EMBASE and CINAHL databases with
additional manual/hand searches for population-based
cohort or case-control studies published in English of
French between January 1980 and January 2015 with a
measure of effect and variance for associations between
arthritis (RA), psoriatic arthritis (PsA), ankylosing
spondylitis (AS), gout or osteoarthritis (OA), adjusted for
at least age and sex. All search screening, data
abstraction quality appraisals were performed
independently by two reviewers. Where appropriate,
random-effects meta-analysis was used to pool results
from studies with a minimum of 10 events.
Results We identified a total of 4, 285 articles; 27 met
review criteria and 25 criteria for meta-analyses. In
studies adjusting for age and sex, MI risk was
significantly increased in RA ( pooled relative risk (RR):
1.69, 95% CI 1.50 to 1.90), gout ( pooled RR: 1.47,
95% CI 1.24 to 1.73), PsA ( pooled RR: 1.41, 95% CI
1.17 to 1.69), OA ( pooled RR: 1.31, 95% CI 1.01 to
1.71) and tended towards increased risk in AS ( pooled
RR: 1.24, 95% CI 0.93 to 1.65). Traditional risk factors
were more prevalent in all types of arthritis. MI risk was
attenuated for each type of arthritis in studies adjusting
for traditional risk factors and remained significantly
increased in RA, PsA and gout.
Conclusions MI risk was consistently increased in
multiple types of arthritis in population-based studies,
and was partially explained by a higher prevalence of
traditional risk factors in all types of arthritis. Findings
support more integrated cardiovascular (CV) prevention
strategies for arthritis populations that target both
reducing inflammation and enhancing management of
traditional CV risk factors.
Despite reductions in mortality over time, ischae-
mic heart disease (IHD) is a major contributor to
the burden from chronic diseases and the leading
cause of death worldwide.1 A number of modifiable
lifestyle factors including smoking, physical inactiv-
ity, overweight/obesity, diabetes, hypertension and
hyperlipidaemia have long been shown to increase
the risk of developing heart disease and are
common targets for prevention strategies.2 More
recently, inflammation has also been shown to play
Schieir O, et al. Ann Rheum Dis 2017;0:1–9. doi:10.1136/annrheumdis-2016-210275
an integral role in the development, instability and
rupture of atherosclerotic plaques leading to acute
ischaemic events.3 4 This has prompted extensive
research examining heart disease risk in inflamma-
tory conditions.
Arthritis is a prevalent inflammatory joint dis-
order affecting the ageing population characterised
by joint pain, stiffness and frequent disability.5 6
Several systematic reviews have examined whether
individual types of arthritis (rheumatoid arthritis
(RA),7 ankylosing spondylitis (AS),8 psoriatic arth-
ritis (PsA),9 gout10 and osteoarthritis (OA)11) are
independently associated with various cardiovascu-
lar (CV) outcomes, with the strongest most consist-
ent evidence pointing towards relationships
between RA and myocardial infarction (MI).7
Previous reviews however included studies with
variable study populations, sources for controls,
designs, outcomes and definitions and had minimal
study inclusion criteria for control of confounding.
Furthermore, focus on individual types of arthritis
in each review did not allow for comparisons of
IHD risk across different types of arthritis. These
limitations make it difficult for clinicians, patients
and policy makers to get a clear sense of whether
and to what extent IHD risk is increased across dif-
ferent arthritis populations and may result in
missed opportunities for preventing or lowering
IHD risk, particularly in non-RA types of arthritis.
The present systematic review and meta-analysis
was undertaken to synthesise best available evi-
dence from population-based studies to quantify
and compare risks for incident MI in five major
types of arthritis (RA, AS, PsA, gout and OA).
PATIENTS AND METHODS
This review was carried out and reported according
to Preferred Reporting Items for Systematic Reviews
and Meta-Analysis12 and the Meta-Analysis of
Observational Studies in Epidemiology13 guidelines.
Data sources and searches
A systematic search developed by an information
specialist for population-based studies estimating
associations between arthritis and incident MI was
performed in MEDLINE, EMBASE and CINAHL
databases. Keyword and major subject headings
were specified for arthritis and for major types of
arthritis (RA, AS, PsA, gout and OA), MI or acute
coronary syndrome (ACS) and cohort or case-
control study designs. Search results were limited
1
 Clinical and epidemiological research
to studies published through January 2015, adults (19+) and
English and French languages (sample MEDLINE search strat-
egy provided as online supplementary material). In addition to
the database search, we performed manual web searches (eg,
Google Scholar) and hand searched bibliographies of retrieved
studies, review articles and screened conference abstracts from
2013 to 2014 American and European rheumatology meetings
(attempted to contact potential abstract authors by email twice
2 weeks apart) to identify potentially relevant studies that were
accepted or in press in a peer-reviewed journal by January
2015.
Study selection
We included cohort and case-control studies that reported a
measure of association (ie, OR, risk ratio, HR) and variability
(SE or 95% CI) for effects of arthritis on incident MI or ACS
defined according to established clinical criteria, physician diag-
nosis, validated administrative billing codes or self-reported
physician diagnosis and adjusted for at least age and sex. MI
was selected as a common objective IHD outcome across studies
for meta-analysis. Studies were excluded if the outcome was a
composite cardiovascular disease end point or if the study did
not include a population-based comparison group. In the event
of multiple publications from the same data source, we included
studies if extractable estimates were reported for different types
of arthritis, but only included the most recent publication if esti-
mates were reported for the same type of arthritis.
Data extraction and quality assessment
The following information was abstracted from each study:
country, funding, study design, data source, sample size,
follow-up period, sample age range, percent female, exposure
and outcome ascertainment and measures of association with
95% CIs, using a predetermined data abstraction template.
Study quality was evaluated using the Newcastle-Ottawa Scale
(NOS).14 The NOS is an 8-item instrument (total score range 0
—lowest to 9—highest quality) evaluating risk of bias in obser-
vational studies in relation to three domains: selection of study
groups (range 0–4), comparability of study groups (range 0–2)
and exposure/outcome ascertainment (range 0–3). NOS quality
scores are presented as part of descriptive summaries for each
study and did not influence decisions to pool studies in
meta-analysis.
All search screening, data abstraction and quality appraisals
was performed independently by two reviewers (OS, CT), with
discrepancies resolved by consensus (n=3).
Data synthesis and analysis
In order to minimise bias that may result from combining small
study effects with high variability, only studies with at least 10
events were eligible to be pooled in meta-analyses. Furthermore,
final decisions on whether or not to pool studies were based on
quantitative assessments of heterogeneity described below and
qualitative assessments based on the number of studies, and the
consistency in direction/magnitude of effect estimates across
studies so that pooled results would be more interpretable.15
The relative risk (RR) was selected as a common measure of
association across studies. Random-effects meta-analysis with
inverse variance weighting16 was used to obtain pooled RRs and
95% CIs by type of arthritis, first in studies adjusting for age
and sex only, and then for studies also adjusting for at least one
of the following traditional risk factors (RF): smoking, obesity/
body mass index (BMI), physical activity, hyperlipidaemia, dia-
betes and high blood pressure. Heterogeneity among studies
2 Schieir O, et al. Ann Rheum Dis 2017;0:1–9. doi:10.1136/annrheumdis-2016-210275
was assessed with Cochrane’s Q statistic and I2 statistic repre-
senting the percentage of heterogeneity across studies attribut-
able to between-study differences.17
We used univariate random-effects meta-regression to
compare associations with MI across arthritis disease types as
well as examined how much arthritis disease type potentially
contributed to overall heterogeneity between studies.
Additional, planned subgroup analyses to examine other poten-
tial sources of heterogeneity between studies included compari-
sons by age, sex, inception versus prevalent arthritis cohorts,
calendar period and geographic region. Changes in pooled
effect sizes after excluding each individual study were performed
to assess if any single study was strongly influencing pooled
results. We assessed publication bias graphically using a funnel
plot where the natural log of the ratio of the RR was plotted
against its SE, and statistically with the Egger test.18 All analyses
were performed using Stata V.12 (StataCorp, College Station,
Texas, USA).
RESULTS
Literature search and study election
Figure 1 summarises study screening and selection results. The
search strategy identified 4, 285 articles, of which 27 met all cri-
teria to be included in the systematic review. Two articles
reported results based on fewer than 10 outcomes,19 20 leaving
25 articles eligible for meta-analysis (RA: 13,21–33 AS: 3,34–36
PsA: 1,28 gout: 6,37–42 OA: 243 44).
Characteristics of included studies published between 1988
and 2015 are presented in table 1: 26 were cohort studies (9
prospective; 17 retrospective) and 1 was a case-control study.
Study populations were from the USA (8), UK (7), Sweden (5),
Canada (3), China (3) and Denmark (1), with participant
follow-up ranging from 1 to 46 years. Thirteen studies included
inception cohorts and 14 prevalent cohorts with arthritis. Of
the 24 studies that reported age entry criteria, 16 had no adult
age limits and 8 were restricted to middle-aged and/or older
adult samples. Higher female-to-male sample ratios were
reported in studies of RA and OA, higher male-to-female
sample ratios in studies of gout and variable sex ratios in studies
of AS and PsA. Traditional risk factors were more prevalent in
all types of arthritis in studies with internal population-based
comparisons.
Associations between incident MI and all major types of
arthritis
Overall, 22/27 (82%) studies reported higher risks for MI in
arthritis groups relative to the general population. Cumulative
incidence of MI based on 6466 MIs in a combined arthritis
sample of 226 962 from 25 studies with available data was
2.85% (95% CI 2.78% to 2.92%). Combined, all five types of
arthritis were associated with an average 50% increased risk for
MI based on 23 studies adjusted for age and sex only (figure 2A),
and an average 30% increased risk for MI based on 17 studies
adjusted for at least one traditional risk factor (figure 2B),
although quantitative estimates of between-study heterogeneity
were high and significant.
Subgroup analyses of incident MI by type of arthritis
We performed subgroup analyses by arthritis disease type. In
studies adjusted for age and sex only, risk of incident MI was
significantly increased in RA, gout, PsA, OA and tended towards
increased risk in AS (figure 2A). Associations with MI were atte-
nuated for all types of arthritis in studies that adjusted for trad-
itional risk factors, and remained significant for RA, gout and

Figure 1 Preferred Reporting Items
for Systematic Reviews and
Meta-Analysis flow diagram
summarising systematic search results.
PsA (figure 2B). Between-study heterogeneity was high and sig-
nificant in RA, gout and AS in studies adjusting for age and sex
only, however, heterogeneity between studies was much lower
and no longer significant for RA and gout in studies with adjust-
ment for traditional RF. Only two studies in OA and AS,
respectively, included adjustment for traditional RF and the dir-
ection or magnitude of results was highly inconsistent between
studies so pooling was not performed for either type of
arthritis.
In meta-regression based on studies adjusting for age and sex
only, estimated risks of MI in PsA, gout, AS and OA did not
differ significantly from RA, and arthritis disease type was not a
significant factor driving heterogeneity between studies
( p=0.198) (table 2). In meta-regression analyses of studies
adjusting for traditional RF limiting to RA, gout and PsA only
(OA and AS omitted due to small number of studies and incon-
sistency across studies), type of arthritis was a significant factor
driving heterogeneity between studies ( p=0.0035) and asso-
ciated risks for MI in gout were on average 20% lower than in
RA (table 2).
Other subgroup and sensitivity analyses
Results of planned subgroup analyses examining other potential
sources of between-study variance including age, sex, arthritis
duration, calendar period and geographic region are presented
Schieir O, et al. Ann Rheum Dis 2017;0:1–9. doi:10.1136/annrheumdis-2016-210275
Clinical and epidemiological research
in table 3. Results of subgroup analyses from studies providing
age-stratified estimates that could be harmonised across studies
showed that while arthritis was associated with increased risks
for incident MI across the adult age span, relative risks tended
to be highest in young, then middle-aged and older adults.
Among studies that provided sex-stratified estimates, pooled
relative risks for MI were significantly increased in both women
and men. Point estimates were consistently higher in women
than in men, but confidence limits between studies overlapped
and differences were inconclusive. There were no differences in
effects of arthritis by duration, calendar period or region.
DISCUSSION
Review results showed that risk of incident MI risk was consist-
ently increased across multiple major types of arthritis in
population-based studies. Traditional CV RF were also more
prevalent in all types of arthritis under study and explained part
of the added risk for MI associated with each type of arthritis.
Included studies were all of moderate to high quality based on
NOS quality scores. Pooled estimates in RA and gout were
based on strong and consistent evidence from multiple studies,
and for PsA based on one large high-quality study. Evidence in
OA and AS was relatively sparse and there were too few studies
with inconsistent results with adjustment for RF to be combined
in meta-analysis. Visual examination of the funnel plot did not
3
4

Clinical and epidemiological research

Table 1 Characteristics of included studies
Higher Higher Higher
Design/ NOS prevalence Age/ ≥1 risk
data Study Age Arthritis Arthritis MI type and Arthritis Arthritis # Additional quality ≥1 risk sex factor
Study Country Funding source period range female % ascertainment ascertainment n events covariates score factor aRR aRR
Rheumatoid arthritis (RA)
Ogdie et al28 UK G, A RC 1994–2010 18–89 70% EHR READ codes MI EHR READ codes 41 752 1032 Smoking, DM, HBP, 4/2/3 (9) Y Y Y
THIN HLD, DMARDs
Ljung et al26 Sweden I RC 2001–2010 ≥18 76% ICD-9–10 codes ACS ICD-7–10 7704 221 COPD, DM, HBP, CBV, 3/2/3 (8) Y Y Y
Population ATH, joint surgery, RA
registers medications
Chung et al21 China G RC 1998–2010 ≥20 77% ICD-9 codes MI ICD-9 29 260 347 DM, HLD, CBV, COPD 4/2/3 (9) Y Y Y
NHIRD and ESRD
Lindhardsen Denmark A RC 1997–2006 ≥16 71% ICD-10 + DMARD MI ICD-10 9921 265 CCI, SES, cardio 4/1/3 (8) NA Y NA
et al25 Population Rx medications
registers
Semb et al29 Sweden A PC 1985–1996 <20+ 69% ICD-8–10 codes MI ICD-8–10 1779 214 None 4/1/3 (8) Y Y NA
AMORIS
Holmqvist Sweden G, I PC 1995–2006 ≥16 71% 1987 ACR criteria MI, IHD ICD-9–10 7469 233 SES, marital status 4/1/3 (8) NA MI: Y NA
et al24 ERAR IHD: Y
Södergren Sweden G,A RC 1985–2003 NR 68% Rheumatologist MI, MONICA 640 35 None 2/1/3 (6) NA Y NA
et al29 RA clinic diagnosis definition
(seropositive)
Solomon Canada NR RC 1999–2003 18+ 71% ICD-9 codes MI ICD-9 codes 25 385 375 None 3/1/2 (6) NA Y NA
et al31 BCLHD
Schieir O, et al. Ann Rheum Dis 2017;0:1–9. doi:10.1136/annrheumdis-2016-210275

Kremers USA G RC 1955–2001 18+ 73% 1987 ACR criteria Hospitalised (H) MI 603 40 HLD, DM, HBP, BMI, 4/2/3 (9) Y H: NU: H: NU: Y
200527 REP unrecognised (U) MI smoking, Y
medical record
Goodson UK G RC 1994–2002 NR 73% Rheumatologist Hospitalised MI 1010 73 None 3/1/2 (6) NA N NA
et al23 RA clinic diagnosis ICD-9–10
Fischer UK G, A RC 1995–2002 <90 NR EHR READ codes MI EHR ICD codes 770 208 Smoking, BMI, HBP, 3/2/2 (7) Y NR Y
et al22 GPRD HLD, CKD, ASA,
NSAID
Turesson Sweden A RC 1997–1999 ≥16 74% 1987 ACR criteria MI ICD-9–10 codes 1022 36 None 4/1/2 (7) NA Y NA
et al33 RA clinics
Solomon USA G, I PC 1976–1996 30–55 100% 1987 ACR criteria MI medical record 527 17 HBP, DM, HLD, BMI, 3/2/3 (8) Y Y Y
et al32 NHS FH, ALC, smoking, PA,
ASA, NSAIDs, steroids,
HRT, supplements
del Rincón USA G, A PC 1996–1997 25–65 62% 1987 ACR criteria MI self-report 236 2 DM, SBP, BMI, 3/2/2 (7) Y NR Y
et al20 ORALE smoking, HLD
Ankylosing spondylitis (AS)
Essers et al36 UK G, I RC 1987–2012 16+ 30% EHR READ codes MI, IHD EHR READ 3809 38 BMI, smoking ALC, 4/2/3 (9) Y MI: N MI: N IHD:
CPRD codes HLD, ESRD, NSAIDs, IHD: Y N
cardio medications
Chou and China G RC 2000–2009 18+ 52% ICD-9 codes ACS ICD-9 6262 221 HBP, DM, HLD, stroke, 4/2/3 (9) Y Y Y
Curhan38 NHIRD cancer

Continued
Schieir O, et al. Ann Rheum Dis 2017;0:1–9. doi:10.1136/annrheumdis-2016-210275

Table 1 Continued
Higher Higher Higher
Design/ NOS prevalence Age/ ≥1 risk
data Study Age Arthritis Arthritis MI type and Arthritis Arthritis # Additional quality ≥1 risk sex factor
Study Country Funding source period range female % ascertainment ascertainment n events covariates score factor aRR aRR
Brophy UK G RC 1999–2010 ≥20 24% EHR READ codes MI EHR READ codes 1686 40 None 3/1/3 (7) Y N N
et al34 EHR
Psoriatic arthritis (PsA)
Ogdie et al28 UK G, A RC 1994–2010 18–89 49% EHR READ codes MI EHR READ codes, 8706 123 Smoking, DM, HBP, 4/2/3 (9) Y Y Y
THIN validated HLD, DMARD use
Li et al19 USA G PC 1991–2009 25–60 100% Self-report Non-fatal MI NR 7 Race, BMI, HLD, HBP, 3/2/3 (8) NR Y Y
NHS II medical records PA, smoking, ALC, FH,
ASA, HRT, OC, VIT
Gout
Kuo et al41 UK G RC 1997–2013 NR 28% EHR READ codes MI EHR READ codes 39 111 1623 BMI, smoking, ALC 4/2/3 (9) Y Y Y
CPRD
Kuo et al42 China G RC 1996–2008 ≥20 30% ICD-9 codes MI ICD-9 codes 26 556 463 DM, stroke, HBP, 4/2/3 (9) Y Y Y
NHIRD ESRD
De Vera Canada G, A RC 1991–2004 ≥65 40% ICD-9 codes MI ICD-9 codes 9642 679 HBP, DM, HLD, COPD, 4/2/3 (9) Y Y Y
et al39 BCLHD CCI, NSAIDs, ASA, women
steroids, HRT, DIU, only
cardio medications
Choi and USA G, I PC 1986–1998 ≥40 0% Medical record Non-fatal MI 1152 23 HBP, HLD, 3/2/3 (8) Y MI: Y MI: Y
Curhan38 HPFUS medical record DM, ASA, DIU,
smoking, BMI, PA,
ALC, FH, diet
Krishnan USA I PC 1982–1999 35–57 0% Self-reported + MI medical records, 1123 118 Centre, BMI, DM, TC, 3/2/3 (8) Y NR Y
et al40 MRFIT serum uric acid death certificates HBP, smoking, ALC,
≥7 mg/dL FH, SCR, ASA, DIU
Abbott USA G PC 1948–1980 30–62 17% Clinical exam MI, CHD clinical 111 22 SBP, TC, smoking, 4/2/2 (9) Y MI: N MI: N

Clinical and epidemiological research

et al37 FHS diuretic naïve exam BMI, DM CHD: Y CHD: Y
Osteoarthritis (OA)
Haugen USA G, A PC 1990–2015 50–75 74% Hand OA CIS/MI medical 726 18 BMI, lipids, DM, HBP, 3/2/3 (8) Y ROA: N ROA: N
et al43 FHS Radiographic (ROA) records, death ALC, smoking, cardio SOA: Y SOA: Y
and/or symptomatic certificates medications and
(SOA) comorbidity
Rahman Canada G, A RC 1991–2009 ≥20 60% OA MI, IHD ICD-9–10 12 745 NR DM, HBP, HLD, COPD, 3/2/3 (8) Y MI: Y MI: N IHD:
et al44 BCLHD ICD-9–10 codes CCI, SES, BMI IHD: Y Y

A, professional association /non-profit agency; ACR, American College of Rheumatology; ACS, acute coronary syndrome; ALC, alcohol intake; AMORIS, Apolipoprotein Mortality Risk Study; ARAMIS, Arthritis, Rheumatism and Aging Medical Information
System; aRR, adjusted relative risk; ASA, aspirin; BCLHD, British Columbia Longitudinal Health Database; BMI, body mass index; CBV, cerebrovascular disease; CCI, Charlson Comorbidity Index; CHD, coronary heart disease; CIS, coronary insufficiency
syndrome; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disorder; CPRD/GPRD, Clinical Practice Research Datalink formerly called the General Practice and Research Database; DIU, diuretics, DM, diabetes mellitus; DMARD,
disease-modifying antirheumatic drug; EHR, electronic health record; ERAR, Early Rheumatoid Arthritis Register; ESRD, end-stage renal disease; FH, family history; FHS, Framingham Heart Study; G, government grant; HBP, high blood pressure; HLD,
hyperlipidaemia; HPFUS, Health Professional Follow-Up Study; HRT, hormone replacement therapy; I, industry; ICD, International Classification of Diseases; IHD, ischaemic heart disease; MI, myocardial infarction; MONICA, Multinational Monitoring of Trends
and determinants in Cardiovascular diseases Study; MRFIT, Multiple Risk Factor Intervention Trial; NA, not applicable; NHIRD, Taiwan National Health Insurance Research Database; NHS, Nurse’s Health Study; NOS, Newcastle-Ottawa Scale; NR, not reported;
NSAIDs, non-steroidal anti-inflammatory drugs; ORALE, Outcome of Rheumatoid Arthritis Longitudinal Evaluation; OC, oral contraceptives; PA, physical activity; PC, prospective cohort; RC, retrospective cohort; REP, Rochester Epidemiology Project; SCR,
serum creatinine; TC, total cholesterol; THIN, The Health Improvement Network; VIT, vitamins.
5
 Clinical and epidemiological research

Figure 2 Forest plots of

population-based studies estimating
risk of incident myocardial infarction
associated with major types of
arthritis. AS, ankylosing spondylitis;
OA, osteoarthritis; PsA, psoriatic
arthritis; RA, rheumatoid arthritis; RR,
relative risk.

6 Schieir O, et al. Ann Rheum Dis 2017;0:1–9. doi:10.1136/annrheumdis-2016-210275

 Clinical and epidemiological research

other associated heart disease RF in the general population.

Table 2 Univariate meta-regression comparing relative effects of
First, contrary to RA where CV risk has been extensively studied
arthritis disease type and potential heterogeneity in estimated
and increased risk is generally well accepted,45 risk in other
associations with incident myocardial infarction (MI)
types of arthritis have received far less attention and are likely
OR 95% CI p Value under-recognised. The present study reported consistent
Rheumatoid arthritis Reference
increased risk of MI across multiple common arthritis disease
Model 1: studies with adjustment for age and sex only (N=23) types. The general public and healthcare providers should be
Gout 0.87 0.70 to 1.09 0.20 made aware of more generalised risks for MI associated with
Psoriatic arthritis 0.84 0.55 to 1.27 0.38 arthritis. Second, results that traditional RF were more prevalent
AS 0.75 0.56 to 1.00 0.05 in all five types of arthritis under study and consistently
OA 0.78 0.56 to 1.08 0.12 explained part of the added risk for MI in each type, point to
Proportion of between-study variance 20%
better management of traditional CV RF as an indirect pathway
explained adjusted R2 to prevent or lower MI risk in arthritis populations. This is
Knapp-Hartung joint test for all covariates p=0.198 important for patients with inflammatory arthritis as clinicians
Model 2: studies with adjustment for traditional risk factors (N=13*)
may focus on controlling inflammation as a sole means of redu-
cing risk. Similarly, in other types of arthritis with a lower
Gout 0.79 0.71 to 0.89 0.001
inflammatory burden, patients may not be perceived as higher
Psoriatic arthritis 0.89 0.68 to 1.15 0.33
risk despite having several traditional RF, some of which may
Proportion of between-study variance 90%
evolve over time secondary to arthritis. For example, disability
explained adjusted R2
may lead to lower physical activity or weight gain,46 47 and
Knapp-Hartung joint test for all covariates 0.004
certain arthritis medications may improve symptoms of inflam-
*OA and AS omitted due to small number of studies and inconsistency across studies. mation but have adverse effects on weight and blood pres-
AS, ankylosing spondylitis; OA, osteoarthritis. sure.48–50 Lastly, together results of meta-analyses of studies
with and without adjustment for traditional RF support
common mechanisms leading to increased risk across different
Table 3 Subgroup analyses of population-based studies estimating types of arthritis (ie, inflammation, traditional RF). However,
risk of incident myocardial infarction associated with major types of the relative contribution of these mechanisms may vary by type
arthritis of arthritis. For example, there was a greater difference in esti-
mated risk for MI in gout than in RA between studies that did
Studies adjusting for age, and did not adjust for RF. The direct contribution of systemic
Studies adjusting for age sex and at least one
and sex only traditional risk factor* inflammation may be higher in RA than in gout, and conversely
the role of traditional RF may be greater in gout.
n Random-effects n Random-effects
Comparison studies RR (95% CI) studies RR (95% CI) Many management guidelines have been developed for indi-
vidual types of arthritis though few, predominantly those for
Age
RA, include recommendations for CV prevention.51 Recently,
<45 3 1.89 (1.69 to 2.12) NA there has been a shift towards developing more integrated CV
45–64 5 1.48 (1.28 to 1.71) prevention strategies for inflammatory conditions. Joint recom-
65+ 8 1.28 (1.19 to 1.38) mendations for managing CV comorbidity in RA, AS and PsA
Sex were first developed by the European League Against
Female 10 1.59 (1.39 to 1.83) 6 1.35 (1.13 to 1.60) Rheumatism in 2010.52 Recommendations for managing
Male 11 1.40 (1.26 to 1.57) 9 1.21 (1.11 to 1.32) common comorbidities in RA, PsA and psoriasis were also made
Cohort type by Canadian rheumatology and dermatology expert panels in
Inception 13 1.45 (1.31 to 1.60) 10 1.31 (1.14 to 1.51) 2015.53 However, gout and OA were not included in either sets
of guidance. Current results combined with increasing preva-
Prevalent 10 1.64 (1.44 to 1.88) 7 1.33 (1.18 to 1.50)
lence, high levels of OA-attributable disability, associations with
Calendar period
obesity and physical inactivity and prolonged treatment with
2005–2015 11 1.44 (1.30 to 1.60) 10 1.31 (1.15 to 1.48)
non-steroidal anti-inflammatory drugs/coxibs,54–57 would
<2005 12 1.66 (1.48 to 1.86) 7 1.31 (1.19 to 1.44) suggest that prevention strategies recommended for other types
Region of arthritis may help reduce risk in gout and OA as well.
North America 8 1.48 (1.25 to 1.76) 8 1.27 (1.12 to 1.41) Targeted education and more effective implementation of CV
Europe 12 1.57 (1.40 to 177) 6 1.34 (1.12 to 1.60) risk management will be important to help mitigate heart
Asia 3 1.51 (1.25 to 1.83) 3 1.31 (1.21 to 1.41) disease risk in arthritis populations. It is now recommended that
rheumatologists screen/manage traditional heart disease RF
*Traditional risk factors: smoking, obesity/body mass index, physical activity,
hyperlipidaemia, diabetes and high blood pressure.
given their expertise with complex arthritis treatment regiments
NA, not applicable; RR, relative risk. and emerging evidence that traditional RF can affect treatment
response to certain therapies.53 However, rheumatologists may
have limited time in a standard visit to incorporate additional
reveal any notable asymmetry ( provided as online comprehensive CV assessments and continued monitoring, as
supplementary material) and the statistical Egger test was not well as keep up with evolving evidence-based standards for
significant ( p=0.255) suggesting a low likelihood for publica- primary and secondary CV prevention. Furthermore, given
tion bias. current shortages of rheumatology specialists in several geo-
Review results have important implications for clinical prac- graphic regions, many types of arthritis, particularly OA and
tice and for planning health services given current and projected gout are often managed outside of rheumatology.58 59 These
increases in arthritis prevalence, and rising trends in obesity and issues point to the need for coordinated efforts between
Schieir O, et al. Ann Rheum Dis 2017;0:1–9. doi:10.1136/annrheumdis-2016-210275 7
 Clinical and epidemiological research
rheumatologists, internists, primary care and other allied health-
care professionals to ensure that excess CV risk in people with
arthritis is appropriately managed.
Strengths of the present review include systematic identifica-
tion and synthesis of best-available evidence from population-
based studies used to estimate effects of five prevalent types of
arthritis on MI. This review is the first to compare MI risk
across different types of arthritis in studies with adjustment for
age and sex only, and with adjustment for traditional RF,
respectively.
Limitations should also be addressed. Relatively few studies
were identified for PsA, AS and OA, and pooled risks of MI for
AS and OA adjusted for traditional RF could not be estimated
due to the small number of studies and inconsistency in results
between studies. Limiting to studies published in English or
French could have led to some bias in pooled effect estimates,
although tests for publication bias were not significant. While
we excluded clear duplicate publications, there could have been
some overlap in study populations in more than one study from
the same country. However, pooled estimates were robust to
sensitivity analyses that eliminated individual studies (available
as online supplementary material). Differences in the types and
proportions of patients being treated were not examined and
could have contributed to heterogeneity. Despite differences in
baseline risks and characteristics of arthritis and heart disease by
age and sex,60 less than half of included studies tested for these
interactions or reported stratified results. Over a third of studies
did not adjust for any traditional RF and studies that did were
often limited to baseline measures or lacked information on
smoking, BMI/obesity and physical activity, increasing potential
for residual confounding in pooled estimates. Given the
common mechanisms linking arthritis and MI discussed above,
risks may also extend to other less prevalent types of arthritis
(eg, systemic lupus erythematosus), inflammatory conditions
other than arthritis and to other vascular end points but were
beyond the scope of the present review and should be explored
in future studies. Large longitudinal population-based studies
with repeated measures examining effects of different types of
arthritis, particularly OA, on IHD and other vascular end points
are needed. Stratified analyses by age and sex and mediation
analyses examining direct and indirect pathways (and potential
variations by type of arthritis) would help inform primary and
secondary prevention strategies.
In conclusion, the present study estimated risk of incident MI
associated with five major types of arthritis from population-
based studies. Results showed that MI risk was consistently
increased in multiple types of arthritis, and was partially
explained by a higher prevalence of traditional RF in all types
of arthritis under study. Study findings support more integrated
CV prevention strategies for arthritis populations that target
both reducing inflammation and enhancing management of
traditional CV RF.
Contributors OS designed and prepared the study protocol, developed the search
strategy in conjunction with an information specialist, performed search screening,
data abstraction, quality appraisal of studies, carried out the analysis and
interpretation of results and drafted the manuscript. She is guarantor. CT performed
search screening, data abstraction, quality appraisal of studies, revised and approved
the manuscript. SH-J, RHG and EMB contributed to the study design, protocol,
analysis plan, interpretation of the results and revised and approved the manuscript.
Funding OS received a doctoral training award from the Fonds de la Recherche du
Québec—Santé. RHG is supported as a Clinician Scientist in the Department of
Family and Community Medicine at the University of Toronto and at St. Michael’s
Hospital.
Competing interests None declared.
8 Schieir O, et al. Ann Rheum Dis 2017;0:1–9. doi:10.1136/annrheumdis-2016-210275
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Add data provided within manuscript or as online
supplementary material.
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