Risk of subsequent ischemic and hemorrhagic stroke in patients hospitalized for immune-mediated diseases: a nationwide follow-up study from Sweden

  • Bengt Zöller1Email author,

    Affiliated with

    • Xinjun Li1,

      Affiliated with

      • Jan Sundquist1, 2 and

        Affiliated with

        • Kristina Sundquist1

          Affiliated with

          BMC Neurology201212:41

          DOI: 10.1186/1471-2377-12-41

          Received: 22 November 2011

          Accepted: 18 June 2012

          Published: 18 June 2012

          Abstract

          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 Wegener´s 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), Crohn´s disease (SIR = 2.15), Grave´s disease (SIR = 2.15), Hashimoto´s 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), Sjögren’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.

          Background

          Ischemic and hemorrhagic stroke are major causes of morbidity and mortality worldwide [1]. During recent years it has become clear that systemic inflammation may enhance atherogenesis [24]. Immune-mediated diseases (IMDs) are a heterogenous group of diseases that are characterized by acute or chronic inflammation [28]. Some IMDs have been associated with an increased risk for cardiovascular disease [28]. 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 [28]. Inflammation may also affect the thrombotic risk by suppressing fibrinolysis, upregulating procoagulants, and downregulating anticoagulants [7]. Thus, certain IMDs such as rheumatoid arthritis (RA) [3, 5, 6, 812] and systemic lupus erythematosus (SLE) [3, 5, 6, 8, 1315] have been associated with an increased risk of cardiovascular disease. Enhanced atherogenesis has also been indicated in other IMDs such as Sjögren´s 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 [19] and rheumatoid arthritis [20].

          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 1987–2008 we have estimated the risk of hospitalization with stroke in patients hospitalized with 32 different IMDs without previous or coexisting stroke.

          Methods

          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 [21]. It included individual-level information on age, sex, occupation, geographic region of residence, hospital diagnoses, and dates of hospital admissions in Sweden (1964–2008), as well as date of emigration, and date and cause of death [21]. The dataset was constructed using several national Swedish data registers (reviewed by Rosen and Hakulinen) [22], 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 [23]. 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 (1987–2008). This study did not include data for hospital outpatients or patients treated at primary health care centers.

          Predictor variable

          The predictor variable was hospitalization for an IMD, diagnosed according to ICD-7, ICD-8, ICD-9, and ICD-10 (Additional file 1 Table S1).

          Outcome variable

          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: 1987–1991, 1992–1996, 1997–2001, 2002–2008.

          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 individual’s 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 husband’s, father’s or mother’s occupation. If that was not possible, they were included in the “non-employed” category. For individuals aged <20 years, parental occupation was used.

          Comorbidity was defined as the first hospital diagnosis at follow up (1987–2008) of the following: 1) chronic lower respiratory diseases (490–496 (ICD-9), and J40–J49 (ICD-10)); 2) obesity (278A (ICD-9), and E65–E68 (ICD-10)); 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 E11-E14 (ICD-10)); 5) hypertension (401–405 (ICD-9), and I10–I15 (ICD-10)); 6) atrial fibrillation (427D (ICD-9), and I48 (ICD-10)); 7) heart failure (428 (ICD-9), and I50 (ICD-10)); 8) renal disease (580–591 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)).

          Statistical analysis

          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 [24]:
          http://static-content.springer.com/image/art%3A10.1186%2F1471-2377-12-41/MediaObjects/12883_2011_592_Equ1_HTML.gif

          Where http://static-content.springer.com/image/art%3A10.1186%2F1471-2377-12-41/MediaObjects/12883_2011_592_IEq1_HTML.gif denotes the total observed number of cases in the study group; http://static-content.springer.com/image/art%3A10.1186%2F1471-2377-12-41/MediaObjects/12883_2011_592_IEq2_HTML.gif (expected number of cases) is calculated by applying stratum-specific standard incidence rates http://static-content.springer.com/image/art%3A10.1186%2F1471-2377-12-41/MediaObjects/12883_2011_592_IEq3_HTML.gif obtained from the reference group to the stratum-specific person-years (n) of risk for the study group; http://static-content.springer.com/image/art%3A10.1186%2F1471-2377-12-41/MediaObjects/12883_2011_592_IEq4_HTML.gif 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 [24]. Ninety-five percent confidence intervals (95% CIs) were calculated assuming a Poisson distribution [24]. All analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC, USA).

          Results

          Table 1 shows the number of people admitted to hospital with each of the selected IMDs during the study 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 1987–2008 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.
          Table 1

          Number of cases hospitalizations of IMD and related conditions, 1987-2008

           

          Men

          Women

          All

          Immune-mediated disease

          No

          %

          No

          %

          No

          %

          Addison disease

          862

          1.05

          1190

          0.89

          2052

          0.95

          Amyotrophic lateral sclerosis

          2376

          2.89

          2055

          1.53

          4431

          2.05

          Ankylosing spondylitis

          2416

          2.94

          1061

          0.79

          3477

          1.61

          Autoimmune hemolytic anemia

          312

          0.38

          391

          0.29

          703

          0.33

          Behcet disease

          146

          0.18

          138

          0.10

          284

          0.13

          Celiac disease

          2639

          3.21

          4249

          3.17

          6888

          3.18

          Chorea minor

          10

          0.01

          25

          0.02

          35

          0.02

          Crohn disease

          9522

          11.58

          10700

          7.98

          20222

          9.35

          Diabetes mellitus type I

          9068

          11.02

          7664

          5.72

          16732

          7.74

          Discoid lupus erythematosus

          54

          0.07

          200

          0.15

          254

          0.12

          Grave disease

          3764

          4.58

          18298

          13.65

          22062

          10.20

          Hashimoto thyroiditis

          1440

          1.75

          5115

          3.82

          6555

          3.03

          Immune thrombocytopenic purpura

          1905

          2.32

          2039

          1.52

          3944

          1.82

          Localized scleroderma

          90

          0.11

          422

          0.31

          512

          0.24

          Lupoid hepatitis

          115

          0.14

          274

          0.20

          389

          0.18

          Multiple sclerosis

          3492

          4.25

          6892

          5.14

          10384

          4.80

          Myasthenia gravis

          935

          1.14

          1149

          0.86

          2084

          0.96

          Pernicious anemia

          1663

          2.02

          1868

          1.39

          3531

          1.63

          Polyarteritis nodosa

          437

          0.53

          386

          0.29

          823

          0.38

          Polymyalgia rheumatica

          5313

          6.46

          11183

          8.34

          16496

          7.63

          Polymyositis/dermatomyositis

          404

          0.49

          667

          0.50

          1071

          0.50

          Primary biliary cirrhosis

          124

          0.15

          675

          0.50

          799

          0.37

          Psoriasis

          4471

          5.44

          4558

          3.40

          9029

          4.17

          Reiter disease

          280

          0.34

          58

          0.04

          338

          0.16

          Rheumatic fever

          236

          0.29

          228

          0.17

          464

          0.21

          Rheumatoid arthritis

          12080

          14.69

          32531

          24.27

          44611

          20.63

          Sarcoidosis

          2847

          3.46

          2518

          1.88

          5365

          2.48

          Sjören syndrome

          125

          0.15

          1175

          0.88

          1300

          0.60

          Systemic lupus erythematosus

          742

          0.90

          3437

          2.56

          4179

          1.93

          Systemic sclerosis

          402

          0.49

          1356

          1.01

          1758

          0.81

          Ulcerative colitis

          12963

          15.76

          10647

          7.94

          23610

          10.92

          Wegener granulomatosis

          1025

          1.25

          884

          0.66

          1909

          0.88

          All

          82258

          100.00

          134033

          100.00

          216291

          100.00

          Table 2

          Number of cases of stroke, 1987-2008

           

          All stroke events

          Subsequent stroke events of auto immune disorders patients

           

          Hemorrhagic stroke

          Ischeamic stroke

          Hemorrhagic stroke

          Ischeamic stroke

          Characteristics

          No.

          %

          No.

          %

          No.

          %

          No.

          %

          Gender

                  

          Men

          36639

          55.1

          216802

          50.7

          566

          38.6

          3216

          34.1

          Women

          29870

          44.9

          211229

          49.3

          902

          61.4

          6221

          65.9

          Age at diagnosis (yrs)

                  

          <50

          5070

          7.6

          13632

          3.2

          73

          5.0

          221

          2.3

          50-59

          6857

          10.3

          29285

          6.8

          120

          8.2

          439

          4.7

          60-69

          12399

          18.6

          71089

          16.6

          249

          17.0

          1263

          13.4

          70-79

          21079

          31.7

          145288

          33.9

          476

          32.4

          3208

          34.0

          > = 80

          21104

          31.7

          168737

          39.4

          550

          37.5

          4306

          45.6

          Period of diagnosis (yrs)

                  

          1987-91

          13074

          19.7

          90088

          21.0

          134

          9.1

          832

          8.8

          1992-96

          15114

          22.7

          110525

          25.8

          299

          20.4

          2183

          23.1

          1997-01

          15773

          23.7

          97993

          22.9

          389

          26.5

          2626

          27.8

          2002-08

          22548

          33.9

          129425

          30.2

          646

          44.0

          3796

          40.2

          Socioeconomic status

                  

          Farmers

          4797

          7.2

          34375

          8.0

          109

          7.4

          773

          8.2

          Self-employed

          4911

          7.4

          31497

          7.4

          95

          6.5

          654

          6.9

          Professionals

          4726

          7.1

          25561

          6.0

          70

          4.8

          438

          4.6

          White collar workers

          18912

          28.4

          119320

          27.9

          476

          32.4

          2773

          29.4

          Workers

          29487

          44.3

          197833

          46.2

          653

          44.5

          4406

          46.7

          Others

          3676

          5.5

          19445

          4.5

          65

          4.4

          393

          4.2

          Region of residence

                  

          Big cities

          22409

          33.7

          145119

          33.9

          429

          29.2

          2915

          30.9

          Northern Sweden

          12936

          19.4

          80680

          18.8

          310

          21.1

          1972

          20.9

          Southern Sweden

          31164

          46.9

          202232

          47.2

          729

          49.7

          4550

          48.2

          Hospitalization for obesity

                  

          Yes

          114

          0.2

          703

          0.2

          2

          0.1

          30

          0.3

          No

          66395

          99.8

          427328

          99.8

          1466

          99.9

          9407

          99.7

          Hospitalization for alcoholism

                  

          Yes

          2265

          3.4

          7448

          1.7

          45

          3.1

          143

          1.5

          No

          64244

          96.6

          420583

          98.3

          1423

          96.9

          9294

          98.5

          Hospitalization for chronic lower respiratory diseases

                  

          Yes

          2067

          3.1

          18287

          4.3

          63

          4.3

          613

          6.5

          No

          64442

          96.9

          409744

          95.7

          1405

          95.7

          8824

          93.5

          Hospitalization for hypertension

                  

          Yes

          2254

          3.4

          16998

          4.0

          48

          3.3

          434

          4.6

          No

          64255

          96.6

          411033

          96.0

          1420

          96.7

          9003

          95.4

          Hospitalization for diabetes type II

                  

          Yes

          2425

          3.6

          28091

          6.6

          77

          5.2

          726

          7.7

          No

          64084

          96.4

          399940

          93.4

          1391

          94.8

          8711

          92.3

          Hospitalization for artrial fibrillation

                  

          Yes

          4174

          6.3

          47257

          11.0

          134

          9.1

          1351

          14.3

          No

          62335

          93.7

          380774

          89.0

          1334

          90.9

          8086

          85.7

          Hospitalization for heart failure

                  

          Yes

          4619

          6.9

          63904

          14.9

          129

          8.8

          1749

          18.5

          No

          61890

          93.1

          364127

          85.1

          1339

          91.2

          7688

          81.5

          Hospitalization for renal disease

                  

          Yes

          2656

          4.0

          19793

          4.6

          105

          7.2

          718

          7.6

          No

          63853

          96.0

          408238

          95.4

          1363

          92.8

          8719

          92.4

          Hospitalization for sepsis

                  

          Yes

          2167

          3.3

          15738

          3.7

          77

          5.2

          615

          6.5

          No

          64342

          96.7

          412293

          96.3

          1391

          94.8

          8822

          93.5

          Hospitalization for coronary heart disease

                  

          Yes

          9323

          14.0

          108895

          25.4

          234

          15.9

          2589

          27.4

          No

          57186

          86.0

          319136

          74.6

          1234

          84.1

          6848

          72.6

          All

          66509

          100.0

          428031

          100.0

          1468

          100.0

          9437

          100.0

          Hemorrhagic stroke

          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 follow-up 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 1–5 years (95% CI 1·69–1·98), 1·63 after 5–10 years (95% CI 1·47–1·80) and 1·47 after 10+ years (95% CI 1·31–1·65).
          Table 3

          SIR for subsequent hemorrhagic stroke of patients with IMD

           

          Follow-up interval (years)

           

          <1

          1-5

          5-10

          > = 10

          All

          Immune-mediated diseases

          O

          SIR

          95% CI

          O

          SIR

          95% CI

          O

          SIR

          95% CI

          O

          SIR

          95% CI

          O

          SIR

          95% CI

          Addison´s disease

          2

          2.70

          0.25

          9.94

          2

          0.64

          0.06

          2.34

          1

          0.42

          0.00

          2.41

          1

          0.55

          0.00

          3.17

          6

          0.74

          0.27

          1.63

          Amyotrophic lateral sclerosis

          1

          0.47

          0.00

          2.68

          2

          1.30

          0.12

          4.78

          1

          1.82

          0.00

          10.42

          0

             

          4

          0.89

          0.23

          2.30

          Ankylosing spondylitis

          6

          8.11

          2.92

          17.76

          15

          3.43

          1.92

          5.68

          7

          1.66

          0.66

          3.44

          14

          2.28

          1.24

          3.84

          42

          2.72

          1.96

          3.67

          Autoimmune hemolytic anemia

          1

          3.13

          0.00

          17.91

          4

          2.96

          0.77

          7.66

          1

          1.15

          0.00

          6.59

          2

          2.99

          0.28

          10.98

          8

          2.49

          1.06

          4.93

          Behcet´s disease

          1

          33.33

          0.01

          191.08

          0

             

          0

             

          0

             

          1

          1.67

          0.00

          9.55

          Celiac disease

          2

          3.57

          0.34

          13.13

          6

          2.08

          0.75

          4.56

          7

          2.69

          1.07

          5.58

          8

          2.65

          1.13

          5.25

          23

          2.54

          1.61

          3.81

          Chorea minor

          0

             

          0

             

          0

             

          0

             

          0

             

          Crohn disease

          5

          1.47

          0.46

          3.46

          47

          2.60

          1.91

          3.46

          19

          1.19

          0.72

          1.87

          24

          1.57

          1.00

          2.34

          95

          1.80

          1.46

          2.21

          Diabetes mellitus type I

          0

             

          2

          2.50

          0.24

          9.19

          1

          1.11

          0.00

          6.37

          2

          1.01

          0.09

          3.70

          5

          1.32

          0.42

          3.10

          Discoid lupus erythematosus

          1

          11.11

          0.00

          63.69

          1

          2.33

          0.00

          13.33

          0

             

          0

             

          2

          1.87

          0.18

          6.87

          Grave´s disease

          8

          1.53

          0.65

          3.02

          58

          1.77

          1.35

          2.29

          48

          1.61

          1.18

          2.13

          41

          1.48

          1.06

          2.02

          155

          1.62

          1.38

          1.90

          Hashimoto´s thyroiditis

          4

          1.47

          0.38

          3.79

          27

          2.01

          1.32

          2.93

          19

          2.10

          1.26

          3.29

          11

          1.37

          0.68

          2.46

          61

          1.84

          1.40

          2.36

          Immune thrombocytopenic purpura

          8

          8.60

          3.67

          17.03

          12

          2.81

          1.45

          4.92

          6

          2.18

          0.79

          4.78

          2

          1.23

          0.12

          4.54

          28

          2.93

          1.94

          4.23

          Localized scleroderma

          0

             

          1

          0.93

          0.00

          5.36

          1

          0.85

          0.00

          4.90

          6

          4.32

          1.55

          9.46

          8

          2.11

          0.90

          4.17

          Lupoid hepatitis

          0

             

          0

             

          0

             

          0

             

          0

             

          Multiple sclerosis

          4

          1.82

          0.47

          4.70

          15

          1.36

          0.76

          2.25

          9

          1.09

          0.49

          2.08

          6

          0.94

          0.34

          2.06

          34

          1.22

          0.84

          1.71

          Myasthenia gravis

          1

          1.22

          0.00

          6.99

          8

          2.09

          0.89

          4.14

          6

          2.17

          0.78

          4.76

          0

             

          15

          1.62

          0.90

          2.68

          Pernicious anemia

          4

          2.15

          0.56

          5.56

          18

          1.67

          0.99

          2.65

          13

          1.52

          0.81

          2.61

          7

          0.99

          0.39

          2.06

          42

          1.49

          1.07

          2.01

          Polyarteritis nodosa

          2

          5.41

          0.51

          19.88

          0

          0.00

          0.54

          2.19

          3

          1.91

          0.36

          5.66

          0

             

          5

          1.00

          0.31

          2.34

          Polymyalgia rheumatica

          21

          2.06

          1.28

          3.16

          78

          1.42

          1.12

          1.77

          65

          1.67

          1.29

          2.13

          40

          1.49

          1.06

          2.03

          204

          1.56

          1.35

          1.79

          Polymyositis/ dermatomyositis

          1

          2.63

          0.00

          15.08

          3

          1.95

          0.37

          5.77

          1

          1.18

          0.00

          6.74

          1

          2.08

          0.00

          11.94

          6

          1.85

          0.66

          4.04

          Primary biliary cirrhosis

          1

          2.08

          0.00

          11.94

          3

          1.76

          0.33

          5.22

          2

          2.17

          0.20

          7.99

          0

             

          6

          1.87

          0.67

          4.10

          Psoriasis

          9

          2.88

          1.31

          5.50

          32

          1.83

          1.25

          2.59

          23

          1.51

          0.95

          2.26

          21

          1.32

          0.81

          2.02

          85

          1.64

          1.31

          2.03

          Reiter´s disease

          0

             

          1

          2.94

          0.00

          16.86

          1

          2.56

          0.00

          14.70

          0

             

          2

          1.42

          0.13

          5.22

          Rheumatic fever

          1

          7.69

          0.00

          44.09

          0

             

          0

             

          1

          1.72

          0.00

          9.88

          2

          1.04

          0.10

          3.81

          Rheumatoid arthritis

          65

          3.27

          2.52

          4.17

          191

          2.03

          1.76

          2.34

          109

          1.92

          1.57

          2.31

          61

          1.78

          1.36

          2.29

          426

          2.08

          1.89

          2.29

          Sarcoidosis

          3

          2.48

          0.47

          7.34

          12

          1.87

          0.96

          3.28

          14

          2.26

          1.23

          3.80

          6

          0.79

          0.28

          1.73

          35

          1.64

          1.14

          2.28

          Sjögren´s syndrome

          0

             

          3

          1.35

          0.25

          4.00

          2

          1.03

          0.10

          3.77

          0

             

          5

          0.81

          0.26

          1.90

          Systemic lupus erythematosus

          9

          8.65

          3.92

          16.50

          13

          2.89

          1.53

          4.95

          4

          1.17

          0.31

          3.03

          6

          1.91

          0.69

          4.19

          32

          2.65

          1.81

          3.74

          Systemic sclerosis

          2

          3.17

          0.30

          11.67

          5

          2.67

          0.84

          6.29

          3

          2.73

          0.51

          8.07

          2

          3.45

          0.33

          12.68

          12

          2.87

          1.48

          5.03

          Ulcerative colitis

          7

          1.45

          0.57

          3.00

          40

          1.45

          1.03

          1.97

          28

          1.21

          0.80

          1.74

          33

          1.44

          0.99

          2.02

          108

          1.37

          1.13

          1.66

          Wegener´s granulomatosis

          6

          5.83

          2.10

          12.76

          3

          0.90

          0.17

          2.67

          2

          1.08

          0.10

          3.95

          0

             

          11

          1.47

          0.73

          2.63

          All

          175

          2.65

          2.27

          3.08

          602

          1.83

          1.69

          1.98

          396

          1.63

          1.47

          1.80

          295

          1.47

          1.31

          1.65

          1468

          1.75

          1.66

          1.84

          O = observed number of cases; SIR = standardized incidence ratio; CI = confidence interval.

          Bold type: 95% CI does not include 1.00.

          Adjusted for age, period, socioeconomic status, region of residence, hospitalization of chronic lower respiratory diseases, obesity, alcoholism, hypertension, diabetes, atrial fibrillation, heart failure, renal disease, sepsis, and coronary heart disease.

          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 Wegener´s granulomatosis. For seven IMDs, the risk of hemorrhagic stroke was increased 10+ years after hospitalization (Table 3): ankylosing spondylitis, celiac disease, Crohn´s 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, 50–59, 60–69, 70–79, and 80+ years) (Additional file 1 Tables S4, S5 and S6).

          Ischemic stroke

          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 1·90–2·14). The overall risk of ischemic stroke decreased over time, to1·50 after 1–5 years (95% CI 1·46–1·55), 1·38 after 5–10 years (95% CI 1·33–1·43) and 1·29 after 10+ years (95% CI 1·23–1·35) (Table 4).

          Ischemic stroke
          Table 4

          SIR for subsequent ischemic stroke of patients with IMD

           

          Follow-up interval (years)

           

          <1

          1-5

          5-10

          > = 10

          All

          Immune-mediated diseases

          O

          SIR

          95% CI

          O

          SIR

          95% CI

          O

          SIR

          95% CI

          O

          SIR

          95% CI

          O

          SIR

          95% CI

          Addison´s disease

          14

          2.71

          1.48

          4.56

          28

          1.17

          0.78

          1.69

          30

          1.90

          1.28

          2.72

          11

          0.97

          0.48

          1.74

          83

          1.48

          1.18

          1.83

          Amyotrophic lateral sclerosis

          7

          0.53

          0.21

          1.10

          16

          1.52

          0.87

          2.47

          7

          1.77

          0.70

          3.67

          2

          1.15

          0.11

          4.23

          32

          1.09

          0.74

          1.54

          Ankylosing spondylitis

          8

          1.62

          0.69

          3.21

          44

          1.55

          1.13

          2.08

          24

          0.98

          0.63

          1.46

          35

          1.08

          0.75

          1.50

          111

          1.23

          1.01

          1.48

          Autoimmune hemolytic anemia

          4

          1.45

          0.38

          3.75

          12

          1.00

          0.51

          1.75

          19

          2.51

          1.51

          3.93

          5

          1.23

          0.39

          2.90

          40

          1.51

          1.08

          2.06

          Behcet´s disease

          1

          4.00

          0.00

          22.93

          1

          0.65

          0.00

          3.70

          0

             

          1

          1.43

          0.00

          8.19

          3

          0.78

          0.15

          2.29

          Celiac disease

          9

          2.17

          0.99

          4.14

          29

          1.28

          0.86

          1.84

          21

          1.17

          0.72

          1.78

          26

          1.47

          0.96

          2.15

          85

          1.36

          1.09

          1.68

          Chorea minor

          0

             

          1

          2.27

          0.00

          13.03

          0

             

          0

             

          1

          1.11

          0.00

          6.37

          Crohn disease

          49

          2.15

          1.59

          2.84

          160

          1.33

          1.13

          1.55

          103

          1.11

          0.91

          1.35

          97

          1.15

          0.93

          1.40

          409

          1.28

          1.16

          1.41

          Diabetes mellitus type I

          1

          6.25

          0.00

          35.83

          2

          0.45

          0.04

          1.65

          5

          2.75

          0.87

          6.46

          17

          5.00

          2.91

          8.02

          25

          2.54

          1.64

          3.76

          Discoid lupus erythematosus

          3

          4.23

          0.80

          12.51

          3

          0.99

          0.19

          2.92

          1

          0.47

          0.00

          2.70

          3

          1.55

          0.29

          4.60

          10

          1.28

          0.61

          2.37

          Grave´s disease

          101

          2.15

          1.76

          2.62

          402

          1.39

          1.26

          1.53

          348

          1.36

          1.22

          1.51

          276

          1.27

          1.12

          1.43

          1127

          1.39

          1.31

          1.48

          Hashimoto´s thyroiditis

          77

          2.99

          2.36

          3.74

          211

          1.73

          1.50

          1.98

          115

          1.39

          1.14

          1.67

          82

          1.28

          1.02

          1.59

          485

          1.64

          1.50

          1.80

          Immune thrombocytopenic purpura

          16

          2.35

          1.34

          3.83

          55

          1.77

          1.33

          2.30

          19

          0.94

          0.57

          1.48

          14

          1.20

          0.65

          2.01

          104

          1.49

          1.22

          1.81

          Localized scleroderma

          2

          1.28

          0.12

          4.71

          13

          1.25

          0.66

          2.14

          18

          1.72

          1.01

          2.72

          11

          1.04

          0.51

          1.86

          44

          1.33

          0.97

          1.79

          Lupoid hepatitis

          3

          4.48

          0.84

          13.25

          4

          1.98

          0.52

          5.12

          0

             

          0

             

          7

          2.10

          0.83

          4.36

          Multiple sclerosis

          40

          3.05

          2.18

          4.15

          73

          1.09

          0.85

          1.37

          55

          1.11

          0.83

          1.44

          35

          0.95

          0.66

          1.32

          203

          1.22

          1.06

          1.40

          Myasthenia gravis

          6

          1.01

          0.36

          2.21

          38

          1.36

          0.96

          1.87

          23

          1.20

          0.76

          1.80

          13

          1.08

          0.57

          1.85

          80

          1.23

          0.97

          1.53

          Pernicious anemia

          25

          1.56

          1.01

          2.31

          138

          1.49

          1.25

          1.76

          89

          1.23

          0.99

          1.52

          74

          1.44

          1.13

          1.80

          326

          1.40

          1.25

          1.56

          Polyarteritis nodosa

          5

          1.23

          0.39

          2.89

          20

          1.30

          0.79

          2.02

          11

          1.05

          0.52

          1.88

          10

          1.13

          0.54

          2.08

          46

          1.19

          0.87

          1.58

          Polymyalgia rheumatica

          165

          1.76

          1.50

          2.05

          761

          1.50

          1.39

          1.61

          529

          1.54

          1.41

          1.68

          322

          1.53

          1.37

          1.71

          1777

          1.54

          1.47

          1.61

          Polymyositis/ dermatomyositis

          10

          3.46

          1.65

          6.39

          13

          1.19

          0.63

          2.03

          6

          1.07

          0.38

          2.34

          5

          1.73

          0.55

          4.07

          34

          1.52

          1.05

          2.13

          Primary biliary cirrhosis

          4

          1.54

          0.40

          3.98

          11

          1.45

          0.72

          2.60

          4

          0.91

          0.24

          2.35

          1

          2.17

          0.00

          12.46

          20

          1.33

          0.81

          2.05

          Psoriasis

          44

          1.92

          1.39

          2.58

          217

          1.65

          1.44

          1.89

          163

          1.53

          1.30

          1.78

          144

          1.41

          1.19

          1.66

          568

          1.56

          1.44

          1.70

          Reiter´s disease

          0

             

          5

          2.02

          0.64

          4.76

          6

          2.47

          0.89

          5.41

          2

          0.56

          0.05

          2.07

          13

          1.47

          0.78

          2.52

          Rheumatic fever

          5

          3.91

          1.23

          9.19

          10

          1.66

          0.79

          3.06

          14

          3.04

          1.65

          5.11

          7

          1.81

          0.72

          3.75

          36

          2.28

          1.59

          3.16

          Rheumatoid arthritis

          345

          2.08

          1.86

          2.31

          1266

          1.66

          1.57

          1.75

          663

          1.45

          1.34

          1.56

          326

          1.30

          1.16

          1.45

          2600

          1.59

          1.53

          1.65

          Sarcoidosis

          9

          0.97

          0.44

          1.85

          70

          1.43

          1.12

          1.81

          51

          1.12

          0.83

          1.47

          56

          1.08

          0.81

          1.40

          186

          1.19

          1.03

          1.38

          Sjögren´s syndrome

          10

          2.57

          1.22

          4.75

          28

          1.38

          0.92

          1.99

          15

          0.96

          0.54

          1.59

          15

          1.26

          0.70

          2.08

          68

          1.31

          1.02

          1.67

          Systemic lupus erythematosus

          19

          2.21

          1.33

          3.46

          88

          2.33

          1.87

          2.87

          54

          1.92

          1.44

          2.51

          30

          1.26

          0.85

          1.80

          191

          1.94

          1.68

          2.24

          Systemic sclerosis

          11

          1.90

          0.94

          3.41

          28

          1.22

          0.81

          1.77

          11

          1.19

          0.59

          2.14

          2

          0.39

          0.04

          1.43

          52

          1.21

          0.90

          1.58

          Ulcerative colitis

          71

          2.15

          1.68

          2.71

          231

          1.27

          1.11

          1.45

          162

          1.09

          0.92

          1.27

          146

          1.05

          0.89

          1.24

          610

          1.21

          1.12

          1.31

          Wegener´s granulomatosis

          11

          1.66

          0.82

          2.98

          12

          0.47

          0.24

          0.83

          26

          1.54

          1.00

          2.25

          12

          1.69

          0.87

          2.96

          61

          1.09

          0.83

          1.40

          All

          1075

          2.02

          1.90

          2.14

          3990

          1.50

          1.46

          1.55

          2592

          1.38

          1.33

          1.43

          1780

          1.29

          1.23

          1.35

          9437

          1.46

          1.43

          1.49

          O = observed number of cases; SIR = standardized incidence ratio; CI = confidence interval.

          Bold type: 95% CI does not include 1.00.

          Adjusted for age, period, socioeconomic status, region of residence, hospitalization of chronic lower respiratory diseases, obesity, alcoholism, hypertension, diabetes, atrial fibrillation, heart failure, renal disease, sepsis, and coronary heart disease.

          The risk of ischemic stroke was ≥2 during the first year after hospitalization for twelve IMDs (Table 4): Addison’s disease, Crohn´s disease, Grave´s disease, Hashimoto´s thyroiditis, immune thrombocytopenic purpura, multiple sclerosis, polymyositis/dermatomyositis, rheumatic fever, rheumatoid arthritis, Sjögren’s 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, Hashimoto’s 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, 50–59, 60–69, 70–79, 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).

          Discussion

          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, 812, 20], systemic lupus erythematosus [3, 5, 6, 8, 1315, 19], Sjögren´s 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 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 [19] and rheumatoid arthritis [20].

          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 [28]. 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 [26]. 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 treatment—corticosteroids promote hemostasis [27]—and the effect of inflammation on coagulation [7] 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 [28, 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 non-steroidal 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, 812, 20] and SLE [3, 5, 6, 8, 1315, 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 [32]. 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, 3335]. 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, 3335], especially for cardiovascular disorders such as stroke, for which approximately 95% of diagnoses have been shown to be correct [3335]. Though, the positive predictive value (PPV) may differ between diagnoses in the Swedish Hospital Discharge Register, the PPV is generally around 85-95% [35].

          Conclusions

          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.

          Abbreviations

          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.

          Declarations

          Acknowledgements

          The authors wish to thank the CPF’s 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 Zöller from the Swedish Heart and Lung Foundation and Region Skåne (REGSKANE-124611), and to Kristina and Jan Sundquist 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). 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.

          Authors’ Affiliations

          (1)
          Center for Primary Health Care Research, Lund University/Region Skåne, Clinical Research Centre
          (2)
          Stanford Prevention Research Centre, Stanford University School of Medicine

          References

          1. Donnan GA, Fisher M, Macleod M, Davis SM: Stroke. Lancet 2008, 371:1612–23.PubMedView Article
          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.PubMedView Article
          4. Hansson GK, Hermansson A: T. The immune system in atherosclerosis. Nature Immunology 2011, 12:204–212.PubMedView Article
          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.PubMedView Article
          6. López-Pedrera C, Pérez-Sánchez C, Ramos-Casals M, Santos-Gonzalez M, Rodriguez-Ariza A, José Cuadrado M: Cardiovascular risk in systemic autoimmune diseases. epigenetic mechanisms of immune regulatory functions, Clin Dev Immunol; 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 immune-mediated inflammatory diseases: incidence, prevalence, natural history, and comorbidities. J Rheumatol Suppl 2010, 85:2–10.PubMedView Article
          9. Lévy 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.PubMed
          10. Solomon DH, Karlson EW, Rimm EB, et al.: Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 2003, 107:1303–7.PubMedView Article
          11. Gabriel SE: Cardiovascular morbidity and mortality in rheumatoid arthritis. Am J Med 2008, 121:S9–14.PubMedView Article
          12. Libby P: Role of inflammation in atherosclerosis associated with rheumatoid arthritis. Am J Med 2008, 121:S21-S31.PubMedView Article
          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.PubMedView Article
          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.PubMedView Article
          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.PubMedView Article
          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.PubMedView Article
          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.PubMedView Article
          18. Vizzardi E, Raddino R, Teli M, Gorga E, Brambilla G: Dei Cas L. Psoriasis and cardiovascular diseases. Acta Cardiol. 2010, 65:337–40.PubMedView Article
          19. Krishnan E: Stroke subtypes among young patients with systematic lupus erythematosus. Am J Medicine 2005, 118:1415.View Article
          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.PubMedView Article
          21. Zöller 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.PubMedView Article
          22. Rosen M, Hakulinen T: Use of disease registers. In Handbook of epidemiology. Edited by: Ahrens W, Pigeot I. Springer, Berlin; 2005:231–52.View Article
          23. The Swedish Hospital Discharge Register 1987–1996: quality and contents. The National Board of Health and Welfare, Stockholm;  .
          24. Rothman KJ, Greenland S: Modern Epidemiology. 2nd edition. Lippincott-Raven, Philadelphia; 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.PubMedView Article
          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.PubMedView Article
          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.PubMed
          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.PubMedView Article
          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.PubMedView Article
          30. Roumie CL, Mitchel EF, Kaltenbach L, Arbogast PG, Gideon P, Griffin MR: Nonaspirin NSAIDs, cyclooxygenase 2 inhibitors, and the risk for stroke. Stroke 2008, 39:2037–45.PubMedView Article
          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.PubMedView Article
          32. National guidelines for stroke care 2009: Basis for control and management. The National Board of Health and Welfare, Stockholm, In Swedish; 2009.
          33. Validity of the diagnoses from the Swedish In-Care Register 1987 and 1995: National Board of Health and Welfare. Stockholm, In Swedish; 2000.
          34. Lindblad U, Råstam 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.PubMed
          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.PubMedView Article
          36. Pre-publication history

            1. The pre-publication history for this paper can be accessed here:http://​www.​biomedcentral.​com/​1471-2377/​12/​41/​prepub

          Copyright

          © Zöller et al.; licensee BioMed Central Ltd. 2012

          This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.