Risk of subsequent ischemic and hemorrhagic stroke in patients hospitalized for immune-mediated diseases: a nationwide follow-up study from Sweden
Risk of subsequent ischemic and hemorrhagic stroke in patients hospitalized for immune- mediated diseases: a nationwide follow-up study from Sweden
Bengt Zller 0
Xinjun Li 0
Jan Sundquist 0
Kristina Sundquist 0
0 Center for Primary Health Care Research, Lund University/Region Skane, Clinical Research Centre , Floor 11, Building 28, Entrance 72 , Skane University Hospital , 205 02, Malmo , Sweden
Background: Certain immune-mediated diseases (IMDs) have been associated with increased risk for cardiovascular disorders. The aim of the present study was to examine whether there is an association between 32 different IMDs and first hospitalization for ischemic or hemorrhagic stroke. Methods: All individuals in Sweden hospitalized with a main diagnosis of IMD (without previous or coexisting stroke), between January 1, 1987 and December 31, 2008 (n = 216,291), were followed for first hospitalization for ischemic or hemorrhagic stroke. The reference population was the total population of Sweden. Adjusted standardized incidence ratios (SIRs) for ischemic and hemorrhagic stroke were calculated. Results: Totally 20 and 15 of the 32 IMDs studied, respectively, were associated with an increased risk of ischemic and hemorrhagic stroke during the follow-up. The overall risks of ischemic and hemorrhagic stroke during the first year after hospitalization for IMD were 2.02 (95 % CI 1.90-2.14) and 2.65 (95 % CI 2.27-3.08), respectively. The overall risk of ischemic or hemorrhagic stroke decreased over time, to 1.50 (95 % CI 1.46-1.55) and 1.83 (95 % CI 1.69-1.98), respectively, after 1-5 years, and 1.29 (95 % CI 1.23-1.35) and 1.47 (95 % CI 1.31-1.65), respectively, after 10+ years. The risk of hemorrhagic stroke was 2 during the first year after hospitalization for seven IMDs: ankylosing spondylitis (SIR = 8.11), immune thrombocytopenic purpura (SIR = 8.60), polymyalgia rheumatica (SIR = 2.06), psoriasis (SIR = 2.88), rheumatoid arthritis (SIR = 3.27), systemic lupus erythematosus (SIR = 8.65), and Wegeners granulomatosis (SIR = 5.83). The risk of ischemic stroke was 2 during the first year after hospitalization for twelve IMDs: Addison's disease (SIR = 2.71), Crohns disease (SIR = 2.15), Graves disease (SIR = 2.15), Hashimotos thyroiditis (SIR = 2.99), immune thrombocytopenic purpura (SIR = 2.35), multiple sclerosis (SIR = 3.05), polymyositis/ dermatomyositis (SIR = 3.46), rheumatic fever (SIR = 3.91), rheumatoid arthritis (SIR = 2.08), Sjgren's syndrome (SIR = 2.57), systemic lupus erythematosus (SIR = 2.21), and ulcerative colitis (SIR = 2.15). Conclusions: Hospitalization for many IMDs is associated with increased risk of ischemic or hemorrhagic stroke. The findings suggest that several IMDs are linked to cerebrovascular disease.
Ischemic and hemorrhagic stroke are major causes of
morbidity and mortality worldwide . During recent
years it has become clear that systemic inflammation may
enhance atherogenesis [2-4]. Immune-mediated diseases
(IMDs) are a heterogenous group of diseases that are
characterized by acute or chronic inflammation [2-8]. Some
IMDs have been associated with an increased risk for
cardiovascular disease [2-8]. IMDs may increase the
cardiovascular disease risk through different mechanisms such
as autoreactive lymphocytes, autoantibodies, autoantigens,
epigenetic mechanisms, and inflammation driving the
formation, progression and rupture of atherosclerotic plaques
[2-8]. Inflammation may also affect the thrombotic risk by
suppressing fibrinolysis, upregulating procoagulants, and
downregulating anticoagulants . Thus, certain IMDs
such as rheumatoid arthritis (RA) [3,5,6,8-12] and
systemic lupus erythematosus (SLE) [3,5,6,8,13-15] have been
associated with an increased risk of cardiovascular disease.
Enhanced atherogenesis has also been indicated in other
IMDs such as Sjgrens disease [3,5,6,16], systemic
vasculitis [3,5], inflammatory bowel disease [3,5,8,17], and
psoriasis [8,18]. As a consequence of this, the risk of stroke has
been reported to be increased in patients with systemic
lupus erythematosus  and rheumatoid arthritis .
We hypothesized that not only IMDs such as SLE and
RA, but also a number of other less well-studied IMDs
have an increased risk of cardiovascular disease. More
specifically, we aimed at determining whether IMDs increase
the risk for hospitalized ischemic or hemorrhagic stroke.
In a nationwide follow-up from 19872008 we have
estimated the risk of hospitalization with stroke in patients
hospitalized with 32 different IMDs without previous or
This study was approved by the Ethics Committee of Lund
University, Sweden. Data used in this study contained
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 dataset was constructed using
several national Swedish data registers (reviewed by Rosen
and Hakulinen) , including, but not limited to, the
Swedish National Population and Housing Census (1960
1990), the Total Population Register, the Multi-Generation
Register, and the Swedish Hospital Discharge Register
. The data were released to us from the National
Board of Health and Welfare and Statistics Sweden.
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 database
at the individual level, these serial numbers were used to
check that individuals with hospital diagnoses of
ischemic or hemorrhagic stroke appeared only once during
the follow-up (for the first hospital diagnosis of ischemic
or hemorrhagic stroke during the study period).
The follow-up period for analysis of data in the present
study started on January 1, 1987 and continued until
hospitalization for ischemic or hemorrhagic stroke, death,
emigration, or the end of the study period (December 31,
2008). Data for first hospitalization for ischemic or
hemorrhagic stroke during the study period were retrieved
from the Hospital Discharge Register (19872008). This
study did not include data for hospital outpatients or
patients treated at primary health care centers.
The predictor variable was hospitalization for an IMD,
diagnosed according to ICD-7, ICD-8, ICD-9, and
ICD10 (Additional file 1 Table S1).
Diagnosis of ischemic stroke was based on the 9th, and
10th revisions of the International Classification of
Diseases (ICD-9, and ICD-10). Cases of ischemic stroke
were identified using the following ICD codes: 433, 434,
435, 437.0, and 437.1 (ICD-9); and I63 (not I636), I65,
I66, I67.2, and I67.8 (ICD-10).
Diagnosis of hemorrhagic stroke was also based on
ICD-9, and ICD-10. Cases of hemorrhagic stroke were
identified using the following ICD codes: 431 and 432
(ICD-9); and I61 and I62 (ICD-10).
Individual-level variables adjusted for in the model
The individual-level variables were sex, age, time period,
geographic region of residence, socioeconomic status
(SES), and comorbidity.
Sex: male or female.
Age was divided into 5-year categories. Subjects of all
ages were included in the study.
Time period was divided into five time periods in order
to allow for adjustment for any change in hospitalization
rates over time: 19871991, 19921996, 19972001,
Geographic region of residence was included as an
individual-level variable to adjust for possible differences in
hospital admissions for ischemic or hemorrhagic stroke
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. We classified
each individuals occupation into one of six categories: 1)
blue-collar worker, 2) white-collar worker, 3) professional,
4) self-employed, 5) farmer, and 6) non-employed
(Individuals without paid employment). Homemakers and
students without an occupation were categorized on the
basis of their husbands, fathers or mothers occupation. If
that was not possible, they were included in the
nonemployed category. For individuals aged <20 years,
parental occupation was used.
Comorbidity was defined as the first hospital diagnosis
at follow up (19872008) of the following: 1) chronic
lower respiratory diseases (490496 (ICD-9), and J40J49
(ICD-10)); 2) obesity (278A (ICD-9), and E65E68
(ICD10)); 3) alcoholism and alcohol-related liver disease (291
and 303 (ICD-9), and F10 and K70 (ICD-10)); 4) type 2
diabetes mellitus (250 (age >29 years) (ICD-9), and
E11E14 (ICD-10)); 5) hypertension (401405 (ICD-9), and
I10I15 (ICD-10)); 6) atrial fibrillation (427D (ICD-9), and
I48 (ICD-10)); 7) heart failure (428 (ICD-9), and I50
(ICD10)); 8) renal disease (580591 and 753B (ICD-9), and
N00-N19, Q61 (ICD-10)); 9) sepsis (036,038 (ICD-9), and
A39-A41 (ICD-10)); and 10) coronary heart disease (410
414 (ICD-9), and I20-I25 (ICD-10)).
Person-years at 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 1987 or later)
until first hospitalization for ischemic or hemorrhagic
stroke, death, emigration, or the end of the study period.
Person years for IMD patients were calculated from
discharge of first hospitalization for IMD (IMD patients with
previous stroke before the first IMD hospitalization or at
the same hospitalization as the first IMD hospitalization,
were excluded). 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 ischemic or hemorrhagic stroke cases using the
indirect standardization method :
Where o Poj 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 j obtained from the reference group to
the stratum-specific person-years (n) 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 following 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 1 shows the number of people admitted to
hospital with each of the selected IMDs during the study
Table 1 Number of cases hospitalizations of IMD and
related conditions, 1987-2008
Immune-mediated disease No
Amyotrophic lateral sclerosis 2376 2.89
9522 11.58 10700 7.98
Diabetes mellitus type I
9068 11.02 7664
Discoid lupus erythematosus 54
Primary biliary cirrhosis
Systemic lupus erythematosus 742
12080 14.69 32531 24.27 44611 20.63
12963 15.76 10647 7.94
82258 100.00 134033 100.00 216291 100.00
18298 13.65 22062 10.20
period. IMD patients with previous stroke before first
hospitalization for IMD or stroke at the same time as
first IMD hospitalization were excluded from Table 1.
Totally 8113 IMD patient with previous or coexisting
ischemic stroke and 1416 with hemorrhagic stroke were
excluded. A total of 216,291 individuals were
hospitalized with an IMD (82,258 males and 134,033 females)
(Table 1). The three most common immune-mediated
diseases were rheumatoid arthritis (44,611 cases),
ulcerative colitis (23,610), and Graves disease (22,062). Totally
66,509 patients with ischemic stroke and 428,031
patients with hemorrhagic strokes from 19872008 were
included (Table 2), of whom 10,905 (9,437 ischemic and
1,468 hemorrhagic strokes) were subsequently admitted
to hospital after a first hospitalization for IMD (Table 2).
The comorbidities (defined as main or second hospital
diagnosis) adjusted for are presented in Table 2.
A total of 66,509 individuals were hospitalized with a main
diagnosis of hemorrhagic stroke (Table 2), of whom 1,468
(2 2 % of hemorrhagic strokes) had been admitted to
hospital due to an IMD (Table 2). The risk of hemorrhagic
stroke was significantly increased during the whole
followup period for 15 of the 32 IMDs studied (Table 3). The
overall risk of hemorrhagic stroke during the first year
after hospitalization for an IMD was 2 65 (95 % CI 2 27
3 08). The overall risk of hemorrhagic stroke decreased
over time, to 1 83 after 15 years (95 % CI 1 691 98),
1 63 after 510 years (95 % CI 1 471 80) and 1 47 after
10+ years (95 % CI 1 311 65).
The risk of hemorrhagic stroke was 2 during the first
year after hospitalization for seven IMD (Table 3):
ankylosing spondylitis, immune thrombocytopenic purpura,
polymyalgia rheumatica, psoriasis, rheumatoid arthritis,
systemic lupus erythematosus, and Wegeners
granulomatosis. For seven IMDs, the risk of hemorrhagic stroke
was increased 10+ years after hospitalization (Table 3):
ankylosing spondylitis, celiac disease, Crohns disease,
Graves disease, localized scleroderma, polymyalgia
rheumatica, and rheumatoid arthritis.
Hemorrhagic stroke and age and sex
The overall risk of hemorrhagic stroke was increased for
both sexes at all different follow-up periods (Additional
file 1 Tables S2 and S3). The overall risk of hemorrhagic
stroke was increased in all age groups for both males
and females (<50, 5059, 6069, 7079, and 80+ years)
(Additional file 1 Tables S4, S5 and S6).
A total of 428,031 individuals were hospitalized with a main
diagnosis of ischemic stroke (Table 2), of whom 9,437
(2 2 % of all ischemic stroke cases) had been admitted to
hospital due to an IMD (Table 2). The variables for which
the SIRs were adjusted are presented in Table 1. The risk of
ischemic stroke was increased during the whole follow-up
period for 20 of the 32 IMDs studied (Table 4). The overall
risk of ischemic stroke during the first year after
hospitalization for an IMD was 2 02 (95 % CI 1 902 14).
The overall risk of ischemic stroke decreased over time,
to1 50 after 15 years (95 % CI 1 461 55), 1 38 after 5
10 years (95 % CI 1 331 43) and 1 29 after 10+ years
(95 % CI 1 231 35) (Table 4).
The risk of ischemic stroke was 2 during the first year
after hospitalization for twelve IMDs (Table 4): Addisons
disease, Crohns disease, Graves disease, Hashimotos
thyroiditis, immune thrombocytopenic purpura, multiple
sclerosis, polymyositis/dermatomyositis, rheumatic fever,
rheumatoid arthritis, Sjgrens syndrome, systemic lupus
erythematosus, and ulcerative colitis. For seven IMDs, the
risk of ischemic stroke was increased 10+ years after
hospitalization: diabetes mellitus type 1, Graves disease,
Hashimotos thyroiditis, pernicious anemia, polymyalgia
rheumatica, psoriasis, and rheumatoid arthritis (Table 4).
Ischemic stroke and age and sex
The overall risk of ischemic or hemorrhagic stroke was
increased for both sexes at all different follow-up periods
(Additional file 1 Tables S7 and S8). The overall risk of
ischemic stroke was increased in all age groups for both
sexes (<50, 5059, 6069, 7079, and 80+ years)
(Additional file 1 Tables S9, S10 and S11).
Time period and hemorrhagic and ischemic stroke
The overall risk for both hemorrhagic and ischemic stroke
was slightly higher between 1987 and 1996 (1.98 95 % CI
1.78-2.20 and 1.51 95 % CI 1.45-1.57, respectively) than
between 1997 and 2008 (1.58 95 % CI 1.48-1.69 and 1.38
95 % CI 1.34-1.41, respectively) (Additional file 1 Tables
S12 and S13).
The present study is the first nationwide study of IMDs and
ischemic and hemorrhagic stroke. The results indicate that
several IMDs increase the risk of hospitalization for both
ischemic and/or hemorrhagic stroke. The relative risk of
ischemic and hemorrhagic stroke during the first year after
hospitalization with certain IMDs was even higher than the
risks associated with many traditional risk factors for
ischemic and hemorrhagic stroke [1,25]. Although it declined
over time, the overall risk of ischemic and hemorrhagic
stroke remained elevated for 10 or more years for some
IMDs. The results of our study are in line with previous
studies linking rheumatoid arthritis [3,5,6,8-12,20], systemic
lupus erythematosus [3,5,6,8,13-15,19], Sjgrens disease
[3,5,6,16], systemic vasculitis [3,5], inflammatory bowel
disease [3,5,8,17], and psoriasis [8,18] to an increased risk of
Table 2 Number of cases of stroke, 1987-2008 (Continued)
9323 14.0 10889525.4 234 15.9 2589 27.4
57186 86.0 31913674.6 1234 84.1 6848 72.6
66509 100.0 428031100.01468 100.0 9437 100.0
cardiovascular disease. However, what distinguishes our
study from these other studies is its comparison of large
numbers of patients and 32 types of IMDs with the general
population in a nationwide setting, as well as the long-term
follow-up of patients and the determination of risk for both
ischemic and hemorrhagic stroke. Moreover, we also found
a number of novel associations between IMDs and ischemic
and hemorrhagic stroke. The results of the present study
suggest that increased risk of subsequent ischemic and
hemorrhagic stroke is a common feature of several IMDs,
not just selected conditions such as systemic lupus
erythematosus  and rheumatoid arthritis .
Although the increased risk of ischemic and hemorrhagic
stroke may have different underlying causes in different
IMDs, a general link between systemic inflammation and
atherothrombosis has been indicated [2-8]. In some
conditions, such as in immune thrombocytopenic purpura,
hemorrhagic stroke may occur as the direct result of
thrombocytopenia. The formation of autoantibodies may,
in special cases, also contribute to stroke . The
increased risk of stroke may be specific for more severe
cases of IMDs, since the patients in our study had been
admitted to hospital. The effects of treatmentcorticosteroids
promote hemostasis and the effect of inflammation
on coagulation  may also contribute to the identified
associations. Hypothetically, the fact that the risk of
ischemic and hemorrhagic stroke decreased over time may
suggest that it is linked to the inflammatory activity of the
IMDs, which is likely to decrease over time due to
treatment. In line with this hypothesis, in several studies disease
activity appears to be linked with atherosclerosis
progression [2-8,28,29]. However, as we lack treatment data, we
cannot prove this hypothesis but in this context it is
interesting that the relative risk of both hemorrhagic and
ischemic stroke was lower between 1997 and 2008 than between
1987 and 1996 (Additional file 1 Tables S12 and S13).
The present study has certain limitations. For example,
we had no data on general cardiovascular disease risk
factors such as weight, smoking, and diet. It is unrealistic to
gather such data for an entire national population.
However, we did adjust for socioeconomic status, which is
associated with risk factors such as smoking. Aspirin and
nonsteroidal anti-inflammatory drugs (NSAID) may affect the
risk of ischemic and hemorrhagic stroke [30,31]. However,
we had no access to treatment data. Adjustment was,
however, made for several comorbidities (chronic lower
respiratory diseases, obesity, alcoholism and alcohol-related liver
disease, type 2 diabetes mellitus, hypertension, atrial
fibrillation, coronary heart diseases, heart failure, renal disease and
sepsis). Still, residual bias may remain due to hospitalization
of the most severe cases with IMD. However, all cases with
previous or coexisting stroke were excluded to avoid
selection bias. Totally, 8113 IMD patients with previous or
coexisting ischemic stroke and 1416 with hemorrhagic stroke
were excluded from the study, which in turn instead may
underestimate the stroke risk. In fact, our results are within
the limit for published cardiovascular disease risk in IMDs
like RA [3,5,6,8-12,20] and SLE [3,5,6,8,13-15,19]. Thus, the
estimated risks of stroke in IMD patients appear to be fairly
valid. Anyway, the present study reflects the real world risks
for stroke among hospitalized IMD (without previous
stroke or at the same time as first hospitalization for IMD).
All cases of ischemic and hemorrhagic stroke in Sweden
should, according to official guidelines, be treated at
hospitals . Moreover, hospitalization incidence rates were
calculated for the whole follow-up period, divided into five
time periods, and adjustments were made for possible
changes in hospitalization rates over time.
This study also has a number of strengths. The study
reflects the situation in real world medicine during
22 years in a country with a high standard in the medical
diagnosis [22,23,33-35]. The study population included
all individuals clinically diagnosed with IMD and
ischemic and hemorrhagic stroke in hospital 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 all subjects for the
whole follow-up period. Data on occupation were 99 2 %
complete (1980 and 1990 censuses), 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 [22,23,33-35], especially for
cardiovascular disorders such as stroke, for which approximately
95 % of diagnoses have been shown to be correct
. Though, the positive predictive value (PPV) may
differ between diagnoses in the Swedish Hospital Discharge
Register, the PPV is generally around 85-95 % .
In summary, the risk of hospitalization for ischemic and
hemorrhagic stroke was, for several immune-mediated
diseases studied, found to be significantly associated. The risk
of ischemic and hemorrhagic stroke during the first year
after hospitalization with an immune-mediated disease was
high for certain IMDs. Although it decreased over time, for
some IMDs the risk of ischemic and hemorrhagic stroke
remained elevated for more than 10 years. The findings of
the present study suggest that many IMDs are linked to
cerebrovascular disease. Future studies could elucidate the
mechanisms behind stroke in specific IMDs.
Additional file 1: Table S1. ICD codes of IMD and related conditions.
Table S2. SIR for subsequent hemorrhagic stroke of male patients with
IMD. Table S3. SIR for subsequent hemorrhagic stroke of female patients
with IMD. Table S4. SIR for subsequent hemorrhagic stroke of patients
with IMD after one year of follow-up. Table S5. SIR for subsequent
hemorrhagic stroke of male patients with IMD after one year of
followup. Table S6. SIR for subsequent hemorrhagic stroke of female patients
with IMD after one year of follow-up. Table S7. SIR for subsequent
ischemic stroke of male patients with IMD. Table S8. SIR for subsequent
ischemic stroke of female patients with IMD. Table 9. SIR for subsequent
ischemic stroke of patients with IMD. Table S10. SIR for subsequent
ischemic stroke of male patients with IMD after one year of follow-up.
Table S11. SIR for subsequent ischemic stroke of female patients with
IMD after one year of follow-up. Table S12. SIR for subsequent
hemorrhagic stroke of patients with IMD after one year of follow-up.
Table S13. SIR for subsequent ischemic stroke of patients with IMD after
one year of follow-up.
CI: Confidence interval; E: Expected; ICD: international classification of
diseases; IMD: immune-mediated disease; O: Observed; RA: rheumatoid
arthritis; SES: socioeconomic status; SIR: standarized incidence ratio;
SLE: systemic lupus erythematosus.
The authors declare that they have no competing interests.
All authors contributed to the conception and design of the study; JS and KS
contributed to the acquisition of data; all authors contributed to the analysis
and interpretation of data; BZ drafted the manuscript; and all authors revised
it critically and approved the final version. All authors had full access to all of
the data (including statistical reports and tables) and take responsibility for
the integrity of the data and the accuracy of its analysis.
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
Welfare. This work was supported by grants to Bengt Zller from the
Swedish Heart and Lung Foundation and Region Skne (REGSKANE-124611),
and to Kristina and Jan Sundquist from the Swedish Research Council
(20083110 and 20082638), the Swedish Council for Working Life and Social
Research (20060386, 20071754 and 20071962), and Formas
(2006-4255-6596-99 and 20071352). No funding bodies played any role in
the design, in the collection, analysis, and interpretation of data or in the
writing and decision to publish this manuscript.
1. Donnan GA , Fisher M , Macleod M , Davis SM : Stroke. Lancet 2008 , 371 : 1612 - 23 .
2. Libby P : Inflammation in atherosclerosis . Nature 2002 , 420 : 868 - 74 .
3. van Leuven SI , Franssen R , Kastelein JJ , Levi M , Stroes ES , Tak PP : Systemic inflammation as a risk factor for atherothrombosis . Rheumatology 2008 , 47 : 3 - 7 .
4. Hansson GK , Hermansson A : T. The immune system in atherosclerosis. Nature Immunology 2011 , 12 : 204 - 212 .
5. Shoenfeld Y , Gerli R , Doria A , Matsuura E , Cerinic MM , Ronda N , Jara LJ , Abu-Shakra M , Meroni PL , Sherer Y : Accelerated atherosclerosis in autoimmune rheumatic diseases . Circulation 2005 , 112 : 3337 - 47 .
6. Lpez-Pedrera C , Prez-Snchez C , Ramos-Casals M , Santos-Gonzalez M , Rodriguez-Ariza A , Jos Cuadrado M : Cardiovascular risk in systemic autoimmune diseases . Clin Dev Immunol : epigenetic mechanisms of immune regulatory functions; 2012 . In press.
7. Xu J , Lupu F , Esmon CT : Inflammation, innate immunity and blood coagulation . Hamostaseologie 2010 , 30 ( 5-6 ): 8 - 9 .
8. El-Gabalawy H , Guenther LC , Bernstein CN : Epidemiology of immunemediated inflammatory diseases: incidence, prevalence, natural history, and comorbidities . J Rheumatol Suppl 2010 , 85 : 2 - 10 .
9. Lvy L , Fautrel B , Barnetche T : Schaeverbeke T. Incidence and risk of fatal myocardial infarction and stroke events in rheumatoid arthritis patients. A systematic review of the literature . Clin Exp Rheumatol 2008 , 26 : 673 - 9 .
10. Solomon DH , Karlson EW , Rimm EB , et al: Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis . Circulation 2003 , 107 : 1303 - 7 .
11. Gabriel SE : Cardiovascular morbidity and mortality in rheumatoid arthritis . Am J Med 2008 , 121 : S9 - 14 .
12. Libby P : Role of inflammation in atherosclerosis associated with rheumatoid arthritis . Am J Med 2008 , 121 : S21 - S31 .
13. Manzi S , Meilahn EN , Rairie JE , et al: Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study . Am J Epidemiol 1997 , 145 : 408 - 15 .
14. Asanuma Y , Oeser A , Shintani AK , Turner E , Olsen N , Fazio S , Linton MF , Raggi P , Stein CM : Premature coronary-artery atherosclerosis in systemic lupus erythematosus . N Engl J Med 2003 , 349 : 2407 - 15 .
15. Roman MJ , Shanker BA , Davis A , et al: Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus . N Engl J Med 2003 , 349 : 2399 - 406 .
16. Vaudo G , Bocci EB , Shoenfeld Y , et al: Precocious intima-media thickening in patients with primary Sjogren's syndrome . Arthritis Rheum 2005 , 52 : 3890 - 7 .
17. van Leuven SI , Hezemans R , Levels JH , Snoek S , Stokkers PC , Hovingh GK , Kastelein JJ , Stroes ES , de Groot E , Hommes DW : Enhanced atherogenesis and altered high density lipoprotein in patients with Crohn's disease . J Lipid Res 2007 , 48 : 2640 - 6 .
18. Vizzardi E , Raddino R , Teli M , Gorga E , Brambilla G : Dei Cas L. Psoriasis and cardiovascular diseases . Acta Cardiol . 2010 , 65 : 337 - 40 .
19. Krishnan E : Stroke subtypes among young patients with systematic lupus erythematosus . Am J Medicine 2005 , 118 : 1415 .
20. Nadareishvili Z , Michaud K , Hallenbeck JM , Wolfe F : Cardiovascular, rheumatologic, and pharmacologic predictors of stroke in patients with rheumatoid arthritis: a nested, case-control study . Arthritis Rheum 2008 , 59 : 1090 - 6 .
21. Zller B , Li X , Sundquist J , Sundquist K : Age- and gender-specific familial risks for venous thromboembolism: a nationwide epidemiological study based on hospitalizations in Sweden . Circulation 2011 , 124 : 1012 - 20 .
22. Rosen M , Hakulinen T : Use of disease registers . In Handbook of epidemiology. Edited by Ahrens W, Pigeot I. Berlin: Springer ; 2005 : 231 - 52 .
23. The Swedish Hospital Discharge Register 1987-1996: quality and contents . Stockholm: The National Board of Health and Welfare; .
24. Rothman KJ , Greenland S : Modern Epidemiology. 2nd edition . Philadelphia: Lippincott-Raven ; 1998 .
25. O'Keefe JH , Carter MD , Lavie CJ : Primary and secondary prevention of cardiovascular diseases: a practical evidence-based approach . Mayo Clin Proc 2009 , 84 : 741 - 57 .
26. Saidi S , Mahjoub T , Almawi WY : Lupus anticoagulants and antiphospholipid antibodies as risk factors for a first episode of ischemic stroke . J Thromb Haemost 2009 , 7 : 1075 - 1080 .
27. Jilma B , Cvitko T , Winter-Fabry A , Petroczi K , Quehenberger P , Blann AD : High dose dexamethasone increases circulating P-selectin and von Willebrand factor levels in healthy men . Thromb Haemost 2005 , 94 : 797 - 801 .
28. Westlake SL , Colebatch AN , Baird J , et al: The effect of methotrexate on cardiovascular disease in patients with rheumatoid arthritis: a systematic literature review . Rheumatology 2010 , 49 : 295 - 307 .
29. Westlake SL , Colebatch AN , Baird J , Edwards CJ , et al: Tumour necrosis factor antagonists and the risk of cardiovascular disease in patients with rheumatoid arthritis: a systematic literature review . Rheumatology 2011 , 50 : 518 - 31 .
30. Roumie CL , Mitchel EF Jr, Kaltenbach L , Arbogast PG , Gideon P , Griffin MR : Nonaspirin NSAIDs, cyclooxygenase 2 inhibitors, and the risk for stroke . Stroke 2008 , 39 : 2037 - 45 .
31. He J , Whelton PK , Vu B , Klag MJ : Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized controlled trials . JAMA 1998 , 280 : 1930 - 5 .
32. National guidelines for stroke care 2009: Basis for control and management . In Swedish: The National Board of Health and Welfare , Stockholm; 2009 .
33. Validity of the diagnoses from the Swedish In-Care Register 1987 and 1995: National Board of Health and Welfare . In Swedish: Stockholm; 2000 .
34. Lindblad U , Rstam L , Ranstam J , Peterson M : Validity of register data on acute myocardial infarction and acute stroke: the Skaraborg Hypertension Project . Scand J Soc Med 1993 , 21 : 3 - 9 .
35. Ludvigsson JF , Andersson E , Ekbom A , Feychting M , Kim JL , Reuterwall C , Heurgren M , Olausson PO : External review and validation of the Swedish national inpatient register . BMC Public Health 2011 , 11 : 450 .