Risk Factors for Cerebrovascular Events in Systemic Lupus Erythematosus: Results from an International, Inception Cohort Study

Abstract

Background/Purpose: Neuropsychiatric (NP) disease in patients with SLE includes cerebrovascular events (CerVE). We determined the frequency, attribution and risk factors for CerVE in a large, multi-ethnic/racial, inception cohort of SLE patients with long-term followup.

Methods: A prospective study of new onset SLE patients was performed by an international network of 32 academic centers in 11 countries. Patients were evaluated at enrollment and annually for up to 17 years. Data were collected at each assessment on demographic and clinical manifestations, medications, SLE disease activity index-2000 (SLEDAI-2K) and Systemic Lupus International Collaborating Clinics (SLICC)/ACR damage index (SDI). Nervous system events were recorded using the ACR case definitions for 19 NP syndromes. These included the following CerVE: (i) Stroke; (ii) Transient ischemia; (iii) Chronic multifocal ischemia; (iv) Subarachnoid and intracranial hemorrhage; (v) Sinus thrombosis. Pre-defined rules determined the attribution of NP events to SLE and non-SLE causes. Demographic variables, clinical variables, medications and NP related lupus autoantibodies were examined as potential predictors of the risk of SLE CerVE by univariate and multivariate Cox regression analyses.

Results: Of 1,826 SLE patients, 88.8% were female, 48.8% Caucasian, 16.8% African, 15.4% Hispanic, 15% Asian and 4% other. At enrollment the mean±SD age was 35.1±13.3 years, SLE duration was 5.6±4.2 months, SLEDAI-2K was 5.3±5.4 and SDI was 0.31±0.73. The mean follow-up was 6.5±4.1 years. Over the study 929 (50.9%) patients had 1,844 NP events of which 573 (31.1%) in 378/1826 (20.7%) patients were attributed to SLE. CerVE were the fourth most frequent NP event: 82/1,826 (4.5%) patients had 109 events of which 103/109 (94.5%) were attributed to SLE and 44 (40.4%) were identified at the enrollment visit. The incidence of first and recurrent CerVE was 5.8/1000 and 32.7/1000 person years respectively. The predominant events were stroke [60/109 (55.0%)] and transient ischemia [28/109 (25.7%)] followed by subarachnoid and intracranial hemorrhage [9/109 (8.3%)], chronic multifocal ischemia [9/109 (8.3%)] and sinus thrombosis [3/109 (2.8%)]. Multivariate analysis identified significant associations between CerVE and concurrent NP events attributed to SLE (HR (95% CI): (3.18; 1.72-5.88), concurrent non-SLE NP events (2.75; 1.55-4.89) (p<0.001), patients of African ancestry at US SLICC sites (2.95; 1.44-6.06) (p=0.003) and increased cumulative organ damage score (excluding NP variables) (p=0.04). There was a significant association between lupus anticoagulant at enrolment and the risk of first CerVE (4.4; 1.8-10.9) but not with recurrent events (0.87; 0.34-2.24) (p=0.012) likely due to the greater use of anticoagulants following the initial CerVE event (94%) compared to at the time of the initial events (37%).

Conclusion: CerVE are the fourth most frequent NP event in SLE, are usually attributable to lupus and occur frequently around the time of SLE diagnosis. Risk factors include other concurrent NP events, African ancestry and lupus anticoagulant.