Age-Dependent Occurrence and Progression of White Matter Hyperintensities in Patients With Systemic Lupus Erythematosus

To elucidate the process of white matter hyperintensities (WMH) deterioration in SLE, we here report the occurrence of WMH on brain magnetic resonance imaging (MRI) by age group and the WMH deterioration rate in patients with SLE. Age-adjusted ratios of periventricular hyperintensities (PVH) and deep white matter hyperintensities (DWMH) in the SLE group (n = 142) were higher than those in the control group (n = 216, p = 0.003 and p < 0.0001, respectively). The difference was remarkable in middle-aged patients ( ≥ 40 and <60 years) (p < 0.0001 for PVH and DWMH). In middle-aged patients with SLE, WMH were associated with factors related to atherosclerosis, including hypertension (OR, 4.0; 95% CI, 1.1–15.8 for PVH and OR, 4.5; 95% CI, 1.1–18.5 for DWMH) and dyslipidemia (OR, 22.2; 95% CI, 1.6–300.5 for PVH). In Kaplan–Meier analysis, the overall rate of one grade WMH deterioration on the Fazekas scale was 8.2% per year after a 15-year follow-up (<60 years, n = 68). WMH in middle-aged patients declined more rapidly than younger patients. Our study reveals that middle-aged patients with SLE pose a risk for developing WMH because of atherosclerotic changes and also can have progressively worsening WMH.


Introduction
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies, immune complex deposition, and multiple target organ damage 1 . SLE predominantly affects women in the age group of 20-40 years 2,3 . A previous international cohort study demonstrated that 40.3% of patients with SLE showed neuropsychiatric symptoms during a mean observation period of 1.9 ± 1.2 years 4 . In these complications, the age-and sex-adjusted risk of cerebrovascular diseases (CVDs) was approximately 1.5 times higher in young patients with SLE (ages 18-50 years) as compared to individuals from the general population 5 . A meta-analysis of prospective longitudinal studies on the general population has shown that white matter hyperintensities (WMH) on brain magnetic resonance imaging (MRI) increase the risk of ischemic stroke (hazard ratio [HR], 3.1; 95% con dence interval [CI], 2.3-4.1) 6,7 . Additionally, the proportion of dementia was approximately three times higher in patients with SLE than randomly selected controls from the general population 8 . In a population-based cohort study, Prins et al. demonstrated that the severity of periventricular WMH increased the risk of dementia (HR, 1.67; 95% CI, 1. 25-2.24) and that the increased risk was partly independent of other structural brain changes found on MRI 9 . In patients with SLE, WMH are the most common brain MRI ndings [10][11][12] . These ndings raise a hypothesis that WMH lead to CVDs and dementia in SLE. However, the development and progression of WMH in SLE are not fully elucidated. In this study, we assessed the burden of WMH between different age groups and analyzed how WMH progressed in patients with SLE.

Results
The occurrence of WMH in patients with SLE by age group Table 1 shows the demographic data of patients at the initial brain MRI in the SLE (n = 142) and control (n = 216) groups. The median age in the SLE and control groups were 39.0 (interquartile range [IQR], 30.0-52.0) and 48.0 (IQR, 34.0-69.0) years, respectively. Age at the initial brain MRI was signi cantly younger in the SLE group compared to the control group (p < 0.0001). SLE group had a signi cantly greater proportion of patients with atherosclerosis-related factors, such as smoking (p = 0.003), hypertension (p = 0.0003), diabetes mellitus (p = 0.039), and dyslipidemia (p = 0.017) than the control group. We compared the ratios of patients with WMH in the SLE and control groups ( Table 2). We used the initial brain MRI images to evaluate WMH in the SLE group. In the SLE group, periventricular hyperintensities (PVH) and deep white matter hyperintensities (DWMH) were observed in 37 (26.1%) and 52 (36.6%) patients, respectively. In the control group, PVH and DWMH were observed in 68 (31.5%) and 74 (34.3%) patients, respectively. The age-adjusted ratios of PVH and DWMH in the SLE group were signi cantly higher than those in the control group (PVH, p = 0.003; DWMH, p < 0.0001). Age-adjusted grades in the SLE group were signi cantly higher than those in the control group (PVH, p = 0.003; DWMH, p < 0.0001). To elucidate the relationship between age and the occurrence of PVH and DWMH in the SLE group, we divided patients into three groups based on their age at the initial brain MRI: age group I, ≥ 10 and < 40 years (SLE, n = 73; control, n = 74); age group II, ≥ 40 and < 60 years (SLE, n = 51; control, n = 64); and age group III, ≥ 60 years (SLE, n = 18; control, n = 78) ( Table 3). In age group I, the ratio of PVH in the SLE group was higher than that in the control group (p = 0.003); however, there was no signi cant betweengroup difference with respect to the ratios of DWMH between the SLE and control groups (p = 0.166). In age group II, the ratios of PVH and DWMH in the SLE group were signi cantly higher than those in the control group (PVH, p < 0.0001; DWMH, p < 0.0001). Conversely, in age group III, the ratio of PVH in the SLE group was signi cantly lower than in the control group (PVH, p < 0.013; DWMH, p = 0.533). These ndings suggested that middle-aged patients (≥ 40 and < 60 years) with SLE constituted a high-risk group for WMH. , showed no association with PVH or DWMH. Additionally, age at the initial brain MRI, duration from onset to the initial brain MRI, and history of antiplatelet or anticoagulant drug intake were not associated with PVH or DWMH. Hypertension was found to be associated with PVH (OR, 4.0; 95% CI, 1.1-15.8) and DWMH (OR, 4.5; 95% CI, 1.1-18.5) ( Table 4) using multivariate analysis. Additionally, dyslipidemia was associated with PVH (OR, 22.6; 95% CI, 1.6-300.5). These ndings suggested that factors related to atherosclerosis, but not an autoimmune abnormality, contributed to the occurrence of WMH in middle-aged patients with SLE.

Progression Of Wmh In Patients With Sle
To elucidate the progression of WMH in SLE, we estimated the rate by which 68 SLE patients aged < 60 years at the initial MRI deteriorated one grade of WMH (PVH and DWMH) on the Fazekas scale. There were no differences in ANA titers, anti-Sm antibodies, aPL antibodies, and SLEDAI between age groups I and II. There were no differences in the usage of antiplatelet and anticoagulant drugs between the two groups. Additionally, the rates of hypertension and dyslipidemia were comparable between age groups I and II (hypertension: 28 (Fig. 1A). When divided into two groups with WMH (n = 26) and without WMH (n = 42) at the initial MRI, Kaplan-Meier analysis showed that the rate of one grade deterioration was more rapid in the group with WMH than in the group without WMH (p < 0.001) (Fig. 1B). Additionally, Kaplan-Meier analysis showed that the rate of one grade deterioration in age group II (n = 29) was higher than in age group I (n = 39, p < 0.001) (Fig. 1C). These ndings indicated that patients with SLE aged < 60 years at the initial MRI showed deterioration in WMH with its continuous extension, and the presence of WMH and the age at the initial MRI were considered as risk factors for deteriorating WMH.

Discussion
In this study, we found that patients with SLE developed PVH and DWMH in middle-age patients (≥ 40 and < 60 years). In the disease control group, only 7.8% and 15.6% of middle-aged patients showed PVH and DWMH, respectively. In a previous study, WMH was rst observed in the general population at the age of 50 and increased as people reached 65-years of age 13 An increase in WMH with age is supported by the results of additional studies 14,15 . In agreement with these ndings, PVH and DWMH were observed in about 80% of older patients (≥ 60 years) in the disease control group. In contrast, we found that 45.1% and 64.7% of middle-aged patients with SLE showed PVH and DWMH, respectively. These ndings showed that patients with SLE developed WMH earlier than individuals in the disease control group. To explore the correlates of WMH in patients with SLE, we analyzed their association with clinical variables in middle-aged patients. We found that hypertension was an independent risk factor for PVH and DWMH, and dyslipidemia was an independent risk factor for PVH. Hypertension, smoking, and diabetes are risk factors for WMH 14,15 . Our data suggest that the aging process concerning WMH begins between 40 and 60 years through atherosclerotic changes in patients with SLE. In previous studies, WMH are categorized as small vessel disease (SVD) 16,17 . SVD mechanism studies have documented cerebrovascular endothelial failure as the initial change in SVD, and age, hypertension, and smoking were also shown to be the risk factors 16 . Conversely, WMH in SLE were classi ed as in ammatory and immunologically mediated SVD with the presence of in ammatory cells in the vessel walls and vasculitis 17 . However, our results did not show any major contribution of autoimmune abnormalities and in ammation to the occurrence of WMH. The proportion of patients with hypertension or dyslipidemia was reported to be signi cantly higher in the SLE group than those in the healthy control group 18,19 . Middle-aged patients (≥ 40 and < 60 years) with SLE could be a high-risk group for WMH because of atherosclerotic changes related to hypertension and dyslipidemia.
In this study, Kaplan-Meier analysis showed that the overall rate of one grade deterioration of WMH on the Fazekas scale was 8.2% per year after a 15-year follow-up. The group with WMH present at the initial MRI nding had a higher deterioration rate than the group without WMH, and middle-aged patients WMH deteriorated more rapidly than younger patients. One may speculate that treatment with corticosteroids negatively affected arteriosclerosis, leading to the rapid progression of WMH in middle-aged patients with SLE. A recent study showed an association between cumulative steroid dose and arteriosclerosis in SLE patients 20 . We were unable to precisely estimate the cumulative dose of corticosteroids in our cohorts because of a partial lack of therapeutic history. We cannot conclude that the corticosteroid dose in uences the formation of WMH because our data showed no difference in the observation period from the onset of disease among the follow-up cohorts. The present results suggest that the age at onset and the presence of brain lesions at the initial MRI are important factors affecting the deterioration of WMH.
In support of this idea, the clinical events of neurological de cits were associated with the temporal change in brain MRI, pointing out the importance of brain MRI imaging at the initial SLE diagnosis 21 .
Our results suggest that middle-aged patients with SLE require therapeutic intervention against hypertension and dyslipidemia to reduce the occurrence of WMH and consequently prevent ischemic stroke and cognitive impairment. However, there were limitations to the interpretations of the present study. One is that this study was a retrospective analysis. Second, the sample size of patients who were followed up for analysis of WMH deterioration was small in this study. Third, there were missing data on measurements of ANA and SLEDAI in the SLE dataset. To test the above hypothesis, it is necessary to validate it using a large multicenter cohort.

Patients
We analyzed 161 patients with SLE who visited the Osaka Medical College Hospital and underwent a brain MRI between April 2012 and June 2018. The inclusion criteria were (1) age of >16 years, (2) SLE diagnosis according to the ACR 1982 revised criteria for SLE 22 , and (3) no obvious evidence of any other disease that could explain SLE-like symptoms. The exclusion criteria were (1) abnormalities on brain MRI, such as hydrocephalus, neoplasm, or metal deposition and (2) history of brain trauma or operation. Of the 161 patients, 142 were women (88.2%). Only female patients were included in this study to standardize patient background characteristics. Of the 142 patients, 110 had undergone a brain MRI to screen brain lesions, whereas 32 had undergone brain MRI to evaluate the cause of neuropsychiatric SLE. Organic brain lesions, including ischemic stroke, were identi ed in ve patients. Seventy-nine patients had undergone brain MRI on more than one occasion (two times in 39 patients, three times in 11, ve times in seven, six times in ve, seven times in four, and >10 times in four In the SLE group, baseline information on age at diagnosis and the titers of ANA, anti-Sm antibodies, and aPL antibodies at the initial brain MRI were collected. Additionally, we collected the history of antiplatelet and anticoagulant drug treatment at the initial brain MRI. In all patients with SLE, administration of corticosteroids was started immediately after the diagnosis of SLE. The patients with SLE continuously received a combination therapy of corticosteroids and a variety of immunosuppressive drugs. The duration of corticosteroid treatment almost matched with disease duration. For the assessment of autoimmune abnormality in SLE at the initial brain MRI, SLEDAI was evaluated 27 . The titers of ANA and anti-double-stranded DNA antibodies were measured by ELISA. Anti-Sm antibodies ≥10.0 U/mL were considered positive.

Assessment of WMH on brain MRI
Diffusion-, T2-, FLAIR, and T2*-weighted sequences (slice thickness: 2 mm) were obtained using 3.0T MRI (GE Signa HDxt). For analyzing WMH, the grades of PVH and DWMH were evaluated by the Fazekas rating scale 28 . PVH was evaluated on FLAIR-weighted transverse images covering the anterior horn and body of the lateral ventricles. DWMH was evaluated on FLAIR-weighted transverse images covering the semioval center. The initial brain MRI was used as the baseline image. To assess temporal changes in WMH, we evaluated the deterioration of WMH grades using the brain MRI data from 68 patients aged <60 years with SLE who repeatedly underwent brain MRI.

Statistical analysis
Categorical and continuous demographic variables in the SLE and control groups were analyzed via Fisher's exact test and Wilcoxon rank-sum test, respectively. The ratio of patients with WMH was analyzed via Fisher's exact test, and the grades of WMH were analyzed via the chi-squared test. The ageadjusted ratios of WMH were conducted by the direct method to the control group, and the data were analyzed using the Cochran-Mantel-Haenszel procedure. We divided the SLE and control groups into three groups based on their age at the initial brain MRI and evaluated the differences between the corresponding sub-groups using Fisher's exact test to evaluate the occurrence of WMH between different age groups. Univariate analysis was conducted to determine the risk factors for WMH in the SLE group using Fisher's exact test; the results are shown as OR and 95% CI. Subsequently, variables associated with p values of <0.25 in the univariate analysis were included in the multivariate logistic regression model to identify factors associated with WMH. We analyzed the progression of WMH grades using Kaplan-Meier curves with the log-rank test. Values are expressed as the median and IQR; p values of <0.05 were considered indicative of statistical signi cance. Statistical analysis was conducted using JMP Pro 14 software (SAS Institute Inc., Cary, NC, USA).

Declarations
Data availability All data analyzed during this study are included in this article.
Author contributions: ES designed the study, collect and analyzed the data, and wrote the manuscript. TT and YN played a role in the data acquisition. SI revised the manuscript. SA designed and supervised the study.