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 234. Immune-mediated diseases (IMDs) are a heterogenous group of diseases that are characterized by acute or chronic inflammation 2345678. Some IMDs have been associated with an increased risk for cardiovascular disease 2345678. 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 2345678. Inflammation may also affect the thrombotic risk by suppressing fibrinolysis, upregulating procoagulants, and downregulating anticoagulants 7. Thus, certain IMDs such as rheumatoid arthritis (RA) 35689101112 and systemic lupus erythematosus (SLE) 3568131415 have been associated with an increased risk of cardiovascular disease. Enhanced atherogenesis has also been indicated in other IMDs such as Sjögren´s disease 35616, systemic vasculitis 35, inflammatory bowel disease 35817, and psoriasis 818. 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.

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.

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.

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 125. 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 3568910111220, systemic lupus erythematosus 356813141519, Sjögren´s disease 35616, systemic vasculitis 35, inflammatory bowel disease 35817, and psoriasis 818 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 2345678. 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 23456782829. 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 3031. 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 3568910111220 and SLE 356813141519. 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 2223333435. 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 2223333435, especially for cardiovascular disorders such as stroke, for which approximately 95% of diagnoses have been shown to be correct 333435. Though, the positive predictive value (PPV) may differ between diagnoses in the Swedish Hospital Discharge Register, the PPV is generally around 85-95% 35.

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.

CI, Confidence interval; E, Expected; ICD, international classification of diseases; IMD, immune-mediated disease; O, Observed; RA, rheumatoid arthritis; SES, socioeconomic status; SIR, standarized incidence ratio; SLE, systemic lupus erythematosus.

The authors declare that they have no competing interests.

All authors contributed to the conception and design of the study; JS and KS contributed to the acquisition of data; all authors contributed to the analysis and interpretation of data; BZ drafted the manuscript; and all authors revised it critically and approved the final version. All authors had full access to all of the data (including statistical reports and tables) and take responsibility for the integrity of the data and the accuracy of its analysis.