Open Access

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

  • Bengt Zöller1Email author,
  • Xinjun Li1,
  • Jan Sundquist1, 2 and
  • Kristina Sundquist1
BMC NeurologyBMC series ¿ open, inclusive and trusted201212:41

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]:
S I R = j 1 J o j j 1 J n j λ j * = o E * , https://static-content.springer.com/image/art%3A10.1186%2F1471-2377-12-41/MediaObjects/12883_2011_Article_592_Equ1_HTML.gif
(1)

Where o = o j https://static-content.springer.com/image/art%3A10.1186%2F1471-2377-12-41/MediaObjects/12883_2011_Article_592_IEq1_HTML.gif denotes the total observed number of cases in the study group; E * https://static-content.springer.com/image/art%3A10.1186%2F1471-2377-12-41/MediaObjects/12883_2011_Article_592_IEq2_HTML.gif (expected number of cases) is calculated by applying stratum-specific standard incidence rates λ j * https://static-content.springer.com/image/art%3A10.1186%2F1471-2377-12-41/MediaObjects/12883_2011_Article_592_IEq3_HTML.gif obtained from the reference group to the stratum-specific person-years (n) of risk for the study group; o j https://static-content.springer.com/image/art%3A10.1186%2F1471-2377-12-41/MediaObjects/12883_2011_Article_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, Skåne University Hospital
(2)
Stanford Prevention Research Centre, Stanford University School of Medicine, Medical School Office Building

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  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

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