Discussion
Our results show that patients with SLE are more likely to suffer from ischaemic and haemorrhagic strokes than patients with non-SLE are. The increased risk of ischaemic stroke remains significant over the 10-year follow-up period. In SLE group, the risk of haemorrhagic stroke is significantly associated with the use of antiplatelets or antithrombotics, while the risk of haemorrhagic stroke is not significantly associated with the anticoagulants use.
Patients with SLE had more stroke events (548 of 8310; 6.6%) than patients without SLE (634 of 16 620; 3.8%), a result consistent with those of other studies. In a previous longitudinal cohort study, the mean standardised incidence ratio of all strokes was 2.02 among patients with SLE.34 Additionally, Wang et al observed an approximately 3.2-fold (5.53 vs 1.74 per person-year) risk of stroke, with an aHR of 2.90, among 13 689 patients with SLE, compared with 54 756 patients with non-SLE.6
Patients who have recently been diagnosed with autoimmune diseases have an increased risk of thrombosis. In patients with SLE, thrombotic events are most prevalent in the first 5 years of the disease.3 Aviña-Zubieta et al observed that the risks of ischaemic stroke and myocardial infarction were highest in the first year after SLE diagnosis, with aHRs of 6.47 and 5.63, respectively.5 A similar finding was disclosed in a Swedish study, with an aHR of 3.70 for ischaemic stroke during the first year of SLE.35 However, the increased thrombotic risk persists throughout the disease course.3
Despite the lifelong persistence of thrombotic events, few long-term studies have examined the association of SLE with stroke. A retrospective cohort study using population database was conducted, and the results showed that SLE and ischaemic stroke are related over a 10 year period. In patients with SLE, even after 10 years, the cumulative incidence of ischaemic strokes was higher than in patients with non-SLE (6.12% vs 3.50%, p<0.001).
Studies have shown that diverse mechanisms, including vasculitis, premature atherosclerosis, antibody alteration, endothelial dysfunction and steroid usage, are involved in stroke pathogenesis in patients with SLE.4 10–14 Old age is also associated with an increased risk for atherosclerosis, while atherothrombotic stroke is the most common type of ischaemic stroke. Previous studies had demonstrated that the risk of thrombosis lasts throughout the course of SLE; although vasculitis-related events are predominant and occur most frequently in the first 5 years, increased risks of atherosclerosis and vessel calcification change are lifelong effects.2 3 Low-dose aspirin may be helpful as a preventive treatment in patients with SLE.17
This study showed that patients with SLE had a significantly increased risk of haemorrhagic stroke (HR=2.24), echoing the result of Wang et al (HR=3.23).6 SLE is independently associated with haemorrhagic stroke, but the pathophysiological relationship between SLE and haemorrhagic stroke remains ambiguous.12 18 36 Although the use of antithrombotics is a risk factor for haemorrhagic stroke, few studies have studied the association between haemorrhagic stroke and antithrombotic use in SLE. According to our findings, patients with SLE on antithrombotics had an increased risk of haemorrhagic stroke; aHRs of antiplatelets and antithrombotics were 1.74 and 1.79, respectively. The association between anticoagulants and haemorrhagic stroke was non-significant in patients with SLE.
Without a doubt, there are classic risk factors for ischaemic stroke. Our results demonstrated an association between the use of antithrombotics and an increased risk of ischaemic stroke, and Manolio et al obtained similar findings. Manolio et al found that aspirin users had increased risks of ischaemic stroke, in addition to haemorrhagic stroke.37 We believe this may be due to indication bias, which occurs when the risk of ischaemic stroke is related to the indication of antithrombotic for other conditions but not to the use of the antithrombotic itself. However, as Manolio et al pointed out, the mechanism underlying this association remains unclear.
Our study has several potential limitations. First, stroke in patients with SLE has multiple pathogeneses; thus, further analysis of each patient’s disease process, smoking habits, serum cholesterol levels and antiphospholipid antibodies may be useful.18 38 Data on the preceding items are unavailable from the NHIRD. In addition, various factors relating to ischaemic stroke pathogenesis are involved in patients with SLE, including vasculitis and long-term steroid use. We need further research to explore the relationship between stroke and SLE in patients with different risk factors or comorbidities. Second, the diagnoses of SLE and stroke in our study were determined entirely from ICD-9-CM codes. Because the NHIRD contains administrative claims data, the diagnostic codes must be reviewed by certified coding specialists for insurance purposes. Moreover, the definitions regarding the diagnoses of SLE and stroke have been validated, having a high sensitivity and positive predictive value,19 39 and have been broadly accepted for use in related research.6 24 25 28–31 However, we could not address unspecified stroke by using the administrative claims data. Finally, a study discovered that SLE flare-ups may be related to a greater number of comorbidities and worse prognosis.15 Our study did not consider disease activity of SLE; therefore, future studies may take disease activity into consideration.
In conclusion, patients with SLE have increased risks of both ischaemic and haemorrhagic stroke, and the increased risk of ischaemic stroke remains significant over 10 years. As far as we know, no previous study of a large population has investigated the associations among SLE, haemorrhagic stroke and the use of antithrombotics. According to our results, patients with SLE on antiplatelets are at a significantly increased risk of haemorrhagic stroke. Low-dose aspirin should be administered carefully and on an individualised basis for patients with SLE, particularly those with a high-risk antiphospholipid antibody profile, to prevent cardiovascular events.