Risk of Subsequent Coronary Heart Disease in Patients Hospitalized for Immune-Mediated Diseases: A Nationwide Follow-Up Study from Sweden
Sundquist K (2012) Risk of Subsequent Coronary Heart Disease in Patients Hospitalized for Immune-Mediated Diseases: A
Nationwide Follow-Up Study from Sweden. PLoS ONE 7(3): e33442. doi:10.1371/journal.pone.0033442
Risk of Subsequent Coronary Heart Disease in Patients Hospitalized for Immune-Mediated Diseases: A Nationwide Follow-Up Study from Sweden
Bengt Zo ller 0
Xinjun Li 0
Jan Sundquist 0
Kristina Sundquist 0
Thomas Forsthuber, University of Texas at San Antonio, United States of America
0 1 Center for Primary Health Care Research, Lund University/Region Ska ne, Clinical Research Centre, Ska ne University Hospital, Malmo , Sweden, 2 Stanford Prevention Research Center, Stanford University School of Medicine , Stanford, California , United States of America
Background: Certain immune-mediated diseases (IMDs), such as rheumatoid arthritis and systemic lupus erythematosus, have been linked to cardiovascular disorders. We examined whether there is an association between 32 different IMDs and risk of subsequent hospitalization for coronary heart disease (CHD) related to coronary atherosclerosis in a nationwide follow up study in Sweden. Methods and Findings: All individuals in Sweden hospitalized with a main diagnosis of an IMD (n = 336,479) without previous or coexisting CHD, between January 1, 1964 and December 31 2008, were followed for first hospitalization for CHD. The reference population was the total population of Sweden. Standardized incidence ratios (SIRs) for CHD were calculated. Overall risk of CHD during the first year after hospitalization for an IMD was 2.92 (95% CI 2.84-2.99). Twentyseven of the 32 IMDs studied were associated with an increased risk of CHD during the first year after hospitalization. The overall risk of CHD decreased over time, from 1.75 after 1-5 years (95% CI 1.73-1.78), to 1.43 after 5-10 years (95% CI 1.411.46) and 1.28 after 10+ years (95% CI 1.26-1.30). Females generally had higher SIRs than males. The IMDs for which the SIRs of CDH were highest during the first year after hospitalization included chorea minor 6.98 (95% CI 1.32-20.65), systemic lupus erythematosus 4.94 (95% CI 4.15-5.83), rheumatic fever 4.65 (95% CI 3.53-6.01), Hashimoto's thyroiditis 4.30 (95% CI 3.87-4.75), polymyositis/dermatomyositis 3.81 (95% CI 2.62-5.35), polyarteritis nodosa 3.81 (95% CI 2.72-5.19), rheumatoid arthritis 3.72 (95% CI 3.56-3.88), systemic sclerosis 3.44 (95% CI 2.86-4.09), primary biliary cirrhosis 3.32 (95% CI 2.34-4.58), and autoimmune hemolytic anemia 3.17 (95% CI 2.16-4.47). Conclusions: Most IMDs are associated with increased risk of CHD in the first year after hospital admission. Our findings suggest that many hospitalized IMDs are tightly linked to coronary atherosclerosis.
Funding: This work was supported by grants from the Swedish Research Council (2008-3110 and 2008-2638), the Swedish Council for Working Life and Social
Research (2006-0386, 2007-1754 and 2007-1962), and Formas (2006-4255-6596-99 and 2007-1352), and from Region Skane (REGSKANE-124611). The funders had
no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Coronary heart disease (CHD) and myocardial infarction are
major causes of morbidity and mortality worldwide . During
recent years it has become clear that systemic inflammation can
enhance atherogenesis ,,. Immune-mediated diseases
(IMDs) are a heterogeneous group of disorders that are
characterized by acute or chronic inflammation. Certain IMDs
have been linked to an increased risk for cardiovascular disease
(CVD) . IMDs may increase the CVD risk through several
mechanisms such as autoantibodies, autoantigens, autoreactive
lymphocytes, epigenetic mechanisms, and inflammatory
components driving the formation, progression and rupture of
atherosclerotic plaques ,,,,,. Inflammation may also
modulate the thrombotic responses by upregulating procoagulants,
downregulating anticoagulants and suppressing fibrinolysis . It
is therefore not surprising that inflammatory IMDs such as
rheumatoid arthritis (RA) ,,,,,,, and
systemic lupus erythematosus (SLE) ,,,,,,
have been linked to an increased risk of CVD. An enhanced
atherogenesis has also been suggested in several other IMDs such
as Sjogrens disease ,,,, systemic vasculitis ,,
inflammatory bowel disease ,,, and psoriasis , .
We postulated that not only immune-mediated diseases such as
RA and SLE, but also a number of other less well studied IMDs or
related diseases have an increased risk of CVD. More specifically
we aimed at determining whether IMDs increase the risk for
hospitalized CHD related to coronary atheroslerosis. In a
nationwide follow-up study from 19642008 we have estimated
the risk of hospitalization with CHD in patients hospitalized with
32 different immune-mediated diseases whithout previous or
MigMed 2 Database
The study was approved by the Ethics Committee at Lund
University and recommendations of the Declaration of Helsinki
were complied with. Informed consent was waived as a
requirement by the ethics committee. Data used in this study
represented information on all individuals registered as residents of
Sweden. It included individual-level information on age, sex,
occupation, geographic region of residence, hospital diagnoses,
and dates of hospital admissions in Sweden (19642008), as well as
date of emigration, and date and cause of death. The datasources
were several national Swedish data registers (reviewed by Rosen
and Hakulinen) , including the Swedish National Population
and Housing Census (19601990), the Total Population Register,
the Multi-Generation register, and the Swedish Hospital
Discharge register (19642008) , provided to us by Statistics
Sweden and the National Board of Health and Welfare.
Information retrieved from the various registers was linked, at
the individual level, via the national 10-digit personal
identification number assigned to each resident of Sweden for his or her
lifetime. Registration numbers were replaced by serial numbers to
preserve anonymity. As well as being used to track all records in
the dataset at the individual level, these serial numbers were used
to check that individuals with hospital diagnoses of CHD appeared
only once in the data set (for the first hospital diagnosis of CHD
during the study period).
The follow-up period for analysis of these data in the present
study started on January 1, 1964 and continued until
hospitalisation for CHD, death, emigration, or the end of the study period
(December 31, 2008). Data for first hospitalisation for CHD (main
or secondary diagnosis) during the study period were retrieved
from the Hospital Discharge Register (19642008), provided to us
by the National Board of Health and Welfare. This register does
not include data for hospital outpatients or patients treated at
primary health care centres.
The predictor variable was first hospitalization for a main
diagnosis of an IMD, diagnosed according to ICD-7, ICD-8,
ICD9 and ICD-10 (Table S1). IMD patients with CHD (main or
secondary diagnosis) before or at the same time as first
hospitalization for IMD (n = 32,352) were excluded.
Diagnosis of CHD was based on the 7th, 8th, 9th and 10th
revisions of the International Classification of Diseases (ICD-7,
ICD-8, ICD-9 and ICD-10). Cases with a main or secondary
diagnosis of CHD were identified using the following ICD codes:
420 (ICD-7); 410-410 (ICD-8); 410-414 (ICD-9); and I20I25
420.1: acute cardiac infarction
420.2: angina pectoris
420.9: old cardiac infarction
410: acute cardiac infarction
411: other acute and subacute forms of CHD
412: old cardiac infarction or chronic CHD
413: angina pectoris
414: asymptomatic CHD
410: acute cardiac infarction
Individual-level variables adjusted for in the model
The individual-level variables included in the analysis were sex,
age, time period, geographic region of residence, socioeconomic
status (SES) and comorbidity.
Sex: male or female.
Time period: time was divided into five periods in order to allow
for adjustment for any change in incidence over time: 19641973,
19741983, 19841993, 19942003, and 20032008.
Age was divided into 5-year categories. Subjects of all ages were
included in the study. Geographic region of residence was
included as an individual-level variable to adjust for possible
differences in hospital admissions for CHD between different
geographic regions in Sweden. It was categorized as 1) large city
(city with a population of .200,000 (i.e., Stockholm, Gothenburg
or Malmo), 2) Southern Sweden (both rural and urban), and 3)
Northern Sweden (both rural and urban).
Occupation was used as a proxy for SES. Occupational data
were retrieved from national census records. We classified each
individuals occupation into one of six categories: 1) manual
worker, 2) lower-level employee, 3) middle-level employee/
professional, 4) self-employed, 5) farmer, and 6) other.
Homemakers and students without an occupation were categorized on
the basis of their fathers or mothers occupation. If that was not
possible, they were included in the other category. Individuals
without paid employment were also included in the other
category. For individuals aged ,20 years, parental occupation was
Comorbidity was defined as the first hospitalization with a main
or secondary diagnosis at follow up from 19642008) of the
following: 1) chronic lower respiratory diseases (500, 501 and 502
(ICD-7), 490493 (ICD-8), 490496 (ICD-9) and J40J49
(ICD10)); 2) obesity (287.00 and 287.99 (ICD-7), 277.99 (ICD-8), 278A
(ICD-9) and E65E68 (ICD-10)); 3) alcoholism (307, 322 and 581
(ICD-7), 291, 303 and 571 (ICD-8), 291 and 303 (ICD-9) and F10
and K70 (ICD-10)); 4) type 2 diabetes mellitus (260 (age.29 yr)
(ICD-7), 250 (age.29 yr) (ICD-8), 250 (age.29 yr) (ICD-9) and
E11E14 (ICD-10); 5) hypertension (440447 (ICD-7), 400 and
402404 (ICD-8), 401405 (ICD-9) and I10I15 (ICD-10)); 6)
atrial fibrillation (433.12 and 433.13 (ICD-7), 427.92 (ICD-8),
427D (ICD-9) and I48 (ICD-10)); 7) heart failure (434.10, 434.20
and 782.40 (ICD-7), 427.00, 427.10, 428.99 and 782.40 (ICD-8),
428 (ICD-9) and I50 (ICD-10)); 8) renal disease (590601 and
757.10 (ICD-7), 580591 and 753.1 (ICD-8), 580591 and 753B
(ICD-9) and N00N19, Q61 (ICD-10)).
Person-years of risk (i.e., number of persons at risk multiplied by
time at risk) were calculated from the time at which subjects were
included in the study (in 1964 or later) until first hospitalization for
a main or secondary diagnosis of CHD, death, emigration, or the
end of the study period (December 31, 2008). Person-years for
IMD patients (without main or secondary diagnosis of CHD
before or at the same time as first hospitalization) were counted
from discharge of the first hospitalization for IMD. The expected
number of cases was based on the number of cases in the reference
group. SIRs were calculated as the ratio of observed (O) and
expected (E) number of CHD cases using the indirect
standardization method :
where O~ P oj denotes the total observed number of cases in the
study group; E (expected number of cases) is calculated by
applying stratum-specific standard incidence rates (lj ) obtained
from the reference group to the stratum-specific person-years (nj)
of risk for the study group; oj represents the observed number of
cases that the cohort subjects contribute to the jth stratum; and J
represents the strata defined by cross-classification of the different
adjustment variables: age, sex, time period, SES, geographic
region of residence, and comorbidity . Ninety-five percent
confidence intervals (95% CIs) were calculated assuming a Poisson
distribution . All analyses were performed using SAS version
9.2 (SAS Institute, Cary, NC, USA).
Table S2 shows the number of people in the study who were
admitted to hospital with any of the selected IMDs during the
study period. Totally 32,352 IMD patients, with a CHD diagnosis
before or at the same time as the first hospitalization for IMD,
were excluded from the study. After this exclusion, a total of
336,479 patients hospitalized with an IMD (128,536 males and
207,943 females) remained in the study (Table S2). The three most
common IMDs were rheumatoid arthritis (62,064 cases), Graves
disease (40,557) and ulcerative colitis (29,698).
Table 1 shows the total number of CHD cases in the entire
population (1,934,822 individuals). Of these, 56,135 had had a
previous hospitalization for IMDs. The comorbidities (defined as
main or second hospital diagnosis) adjusted for are presented in
Table 1. The risk of CHD was increased during the first year after
hospitalization for 27 of the 32 IMDs studied (Table 2). The
overall risk of CHD during the first year after hospitalization for
an IMD was 2.92 (95% confidence interval (CI) 2.842.99). The
overall risk of CHD decreased over time, from 1.75 after 15 years
(95% CI 1.731.78), to 1.43 after 510 years (95% CI 1.411.46)
and 1.28 after 10+ years (95% CI 1.261.30).
The risk of CHD was $3 during the first year after
hospitalization for 13 IMDs (Table 2). For 18 IMDs, the risk of
CHD was increased 10+ years after hospitalization, i.e., ankylosing
spondylitis, Behcets disease, type 1 diabetes mellitus, discoid lupus
erythematosus, Gravesdisease, Hashimotos thyroiditis, immune
thrombocytopenic purpura, pernicious anemia, polymyalgia
rheumatica, polymyositis/dermatomyositis, psoriasis, rheumatic
fever, rheumatoid arthritis, Sjogrens syndrome, systemic lupus
erythematosus, systemic sclerosis, ulcerative colitis and Wegeners
granulomatosis (Table 2).
The SIR for CHD was highest among individuals younger than
50 years but was increased also among older IMD patients
(Table 3). The overall risk of CHD was increased in both males
and females at different times after hospitalization with an IMD
(Tables S3 and S4) and in all studied age groups (,50, 5059, 60
69,7079 and .80 years) (Tables S5 and S6). The SIR for CHD
tended to be slightly higher for females with IMDs than males with
IMDs (Tables S3, S4, S5, and S6). The overall risk of CHD for
females during the first year after hospitalization for an IMD was
3.06 (95% CI 2.963.17) versus 2.72 (95% CI 2.612.83) for
The overall risk of CHD was somewhat lower between 1994
and 2008 (SIR 1.42, 95% CI 1.401.44) than between 1964 and
1993 (SIR 1.58, 95% CI 1.561.60) (Table S7). This was observed
both for females and males (Tables S8 and S9).
Overall risks of CHD were slightly higher for IMD patients who
stayed in hospital for less than 7 days (overall SIR 1.63, 95% CI
1.611.64), compared to those who stayed 7 days or more (SIR
1.41, 95% CI 1.401.44) (Table S10).
The present study is the first nationwide study of
immunemediated diseases and CHD. The results indicate that hospitalized
immune-mediated diseases affect the risk of hospitalization for
CHD in both males and females in all studied ages. The relative
risk of hospitalized CHD during the first year after hospitalization
with an IMD was even higher than for many traditional risk
factors for CHD . Although the CHD risk declined over time,
the overall risk of CHD remained increased for 10 or more years.
The results of our study are in line with previous studies linking
rheumatoid arthritis , systemic lupus
erythematosus ,,,,,,, Sjo grens disease
,,,, systemic vasculitis ,, inflammatory bowel
disease , and psoriasis , to an increased risk of
CVD. However, our study is unique because it includes a
comparison of patients with a wide spectrum of IMDs with the
general population in a nationwide setting, as well as a long-term
follow-up of patients for CHD. Moreover, we also found a number
of novel associations between IMDs and CHD. The results of the
present study suggest that CHD due to coronary atherosclerosis is
a common feature of several hospitalized IMDs. This risk is not
limited to the period immediately following hospital admission: in
the case of IMD for which there were sufficient numbers of cases
for analysis it was sustained over time.
The increased risk of CHD may have different underlying
causes in different IMDs although a general link between systemic
inflammation and atherothrombosis is well established
,,,,,. It may be a reflection of more extreme
cases of IMDs with severe inflammation, since the patients in our
study had been admitted to hospital. The risk was also slightly
higher among IMD patients who stayed in hospital for less than 7
days (SIR 1.63), compared to those who stayed 7 days or more
(SIR 1.41). Although we cannot explain these findings, it is
possible that those patients who stayed for more than a week also
received some treatment for CHD risk factors, which could have
decreased their CHD risk.
The effects of treatment (corticosteroids promote hemostasis)
may contribute to the identified associations . The fact that the
risk of CHD decreased over time may suggest that the CHD risk is
linked to the inflammatory activity of the IMD, which is likely to
decrease over time due to treatment. In line with this hypothesis,
several studies have suggested that disease activity is linked with
atherosclerosis progression ,. Moreover, the risk of CHD
for IMD patients was somewhat lower between 1994 and 2008
(SIR 1.42) than between 1964 and 1993 (SIR 1.58), which may
reflect a general decrease in CHD rates over time or progressively
more intensive antiinflammatoric treatment regimes in the recent
decades. However, as we lack treatment data, we cannot test this
The present study has certain limitations. For example, we had
no data on general cardiovascular risk factors such as body mass
All CHD events
Subsequent CHD events of IMD patients
Follow-up interval (years)
. = 10
index (BMI), smoking, and diet, because it would be unrealistic to
gather such data for an entire national population. However, we
did adjust for socioeconomic status, which is associated with
factors such as smoking. Adjustment was also made for eight
different comorbidities (COPD, obesity, alcoholism and
alcoholrelated liver disease, hypertension, type 2 diabetes mellitus, atrial
fibrillation, heart failure, and renal disease). We had no access to
outpatient data, which means that only the most severe cases of
immune-mediated diseases (i.e. those requiring hospitalization)
were included in the analyses. Thus, although we adjusted for
Age at diagnosis of CHD (years)
. = 70
comorbidites residual confounding may still be present. However,
we excluded all IMD cases with previous or coexisting CHD
(n = 32,352) in order to minimize the risk for selection bias, which
instead may have lead to an underestimation of the actual CHD
risk in IMD patients. In fact, the relative risks for CHD among
patients with RA or SLE in the present study are within the range
previously reported for CVD for these two immune-mediated
diseases ,,,,,,,,,,. It is
therefore likely that risk estimates in the present study are fairly valid.
Moreover, the present findings reflect the real world and the risk
for subsequent CHD among hospitalized IMD patients without
previous or coexisting CHD. Another problem might be that not
all CHD are hospitalized. However, most cases of acute coronary
syndrome should have been treated at hospitals in Sweden during
the study period . Moreover, incidence rates were calculated
for the whole follow-up period, divided into time periods, and
adjustments were made for possible changes in hospitalization
rates over time due to different admission criteria.
This study also had a number of strengths. For instance, the
study population included all patients hospitalized with IMD
(without previous or coexisting CHD) and subsequently with CHD
in Sweden during the study period, which eliminated recall bias.
Because of the personal identification number assigned to each
resident in Sweden, it was possible to trace the records for every
subject for the whole follow-up period. Data on occupation were
99.2% complete (1980 and 1990 census), which enabled us to
adjust our models for socioeconomic status. A further strength of
the present study was the use of validated hospital discharge data.
The Hospital Discharge Register has high validity
,,,, especially for cardiovascular disorders such
as stroke, and myocardial infarction, for which approximately
95% of diagnoses have been shown to be correct ,,.
Although, the positive predictive value (PPV) may differ between
diagnoses in the Swedish Hospital Dicharge Register, the PPV is
generally around 8595% .
In summary, the risk of hospitalization for CHD was, for most
immune-mediated diseases, found to be significantly increased
during the first year after hospitalization. The risk for CHD
decreased with time, but for many IMDs persisted for more than
10 years. The findings of the present study suggest that many
hospitalized IMDs are tightly linked to coronary atherosclerosis.
Further studies need to clarify the mechanisms behind our
SIR for subsequent CHD of male patients with IMD.
SIR for subsequent CHD of female patients with
Table S7 SIR for subsequent CHD of patients with IMD after
one year of follow-up for time periods 19641993 and 19942008.
Table S8 SIR for subsequent CHD of male patients with IMD
after one year of follow-up for time periods 19641993 and 1994
Table S9 SIR for subsequent CHD of female patients with IMD
after one year of follow-up for time periods 19641993 and 1994
Table S10 SIR for all subsequent CHD of patients with IMD
hospitalization length ,7 days or 7 or more days.
The authors wish to thank the CPFs Science Editor Stephen Gilliver for
his useful comments on the text. The registers used in the present study are
maintained by Statistics Sweden and the National Board of Health and
Conceived and designed the experiments: BZ XL JS KS. Performed the
experiments: BZ XL JS KS. Analyzed the data: BZ XL JS KS.
Contributed reagents/materials/analysis tools: JS KS. Wrote the paper:
BZ XL JS KS.
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