In research conducted at the National University of Singapore, reduction in systemic lupus erythematosus (SLE) disease activity was associated with increases in prefrontal white matter volumes (WMV), reflecting a focal partial recovery of the WMV loss that was documented in early SLE disease. These radiographic diagnostic findings were published in Nature Scientific Reports.1

The pathogenesis of the neurologic manifestations of SLE is not completely understood. Autoimmune mechanisms, vasculopathy, and secondary infections due to chronic immunosuppressive therapy may play a role in some cases of neuropsychiatric SLE (NPSLE). 2

One of the most reported neurologic imaging abnormalities in NPSLE is cerebral atrophy secondary to loss of WMV and gray matter volume (GMV), which is associated in some studies with cognitive dysfunction.3 It was postulated by Anselm Mak, MD, from the Department of Medicine at the Yoong Loo Lin School of Medicine, National University of Singapore, and colleagues that the loss of WMV and GMV may be partially reversible with early control of SLE disease activity.

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To confirm that patients with newly diagnosed SLE would have radiographically detectable decreases in WMV and GMV, and to test whether adequate control of disease activity would correlate with increases in WMV and GMV in patients with SLE, the researchers prospectively recruited 14 patients fulfilling the American College of Rheumatology classification criteria of SLE, as well as 14 healthy controls matched for age, education level, and gender.  

Patients with SLE who had a history of neurological, psychiatric, or cardiovascular disease, and those who were serologically positive for anti-cardiolipin antibodies and lupus anticoagulant were excluded from the study in order to limit potential confounders.

All study participants had 2 magnetic resonance imaging (MRI) scans, separated by at least 6 months. Voxel-based morphometry was used in image analysis to quantify cerebral volumes.

SLE disease activity was assessed on the day of the baseline MRI scan using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). The mean interval time between the initial diagnosis of SLE and the first MRI scan was 36.86 days ± 35.5 (range 8–143 days). As per hospital policy, patients also underwent laboratory testing for complement factors, anti-double stranded DNA levels, fasting glucose levels, and lipid profiles. All subsequent  SLE management was left to the discretion of the attending rheumatologist.

Patients with SLE were asked to return for a second MRI scan once they had achieved SLEDAI scores of less than 4 and once more than 6 months had elapsed since the baseline MRI was taken. This was to ensure that an adequate amount of time had passed for SLE disease activity to improve and to allow for the detection of changes in cerebral volumes. SLE disease activity and laboratory evaluation was repeated on the same day as the second scan.

The study authors found that study participants with SLE had lower GMV, primarily in the frontal regions, when compared to matched controls at both the baseline MRI scan and also in the second repeat scan. Study participants with SLE also had lower WMV in the bilateral superior longitudinal fasciculus, corticospinal tract, cingulum cingulate gyrus, and inferior fronto-occipital fasciculus when compared with matched healthy controls.

Most notably, researchers found that GMV in the left superior frontal gyrus was increased at the time of the second MRI scan when SLEDAI scores had decreased. The increased GMV in the left superior frontal gyrus was found to be significantly associated with a reduction in SLEDAI scores in SLE study participants (P< .05). There was no detected change in WMVs between the first MRI scan and the second scan.

“I would expect an improvement in cognitive function subserved by the frontal lobe after SLE disease activity has improved with immunosuppressive therapy in the SLE group if we had a chance to perform comprehensive neuropsychological test[s] for our patients before and after treatment”, study author Dr Mak said in an email to Rheumatology Advisor.

Summary and Clinical Applicability

In this prospective study, researchers found that participants with SLE had reduced GMV and WMV at the time of baseline MRI scanning when compared with healthy matched controls. After SLE participants achieved SLEDAI scores <4, repeat MRI scans revealed increases in GMV. most notably in the left superior frontal gyrus, a region that has been implicated in higher level executive functioning.  

These results suggest that early diagnosis of SLE, with rapid control of disease activity, may play an increasingly important role in preventing further NPSLE disease morbidity. 

“Our finding clearly demonstrates, at least structurally, some degree of neuroplasticity in terms of improvement in the volume of the frontal gray matter”, Dr Mak indicated in an email to Rheumatology Advisor.


1.  Mak, A. et al. Early cerebral volume reductions and their associations with reduced lupus disease activity in patients with newly-diagnosed systemic lupus erythematosusSci. Rep. 6, 22231;doi: 10.1038/srep22231 (2016).

2.  Bhattacharyya S, Helfgott SM. Neurologic complications of systemic lupus erythematosus, sjögren syndrome, and rheumatoid arthritis. Semin Neurol. 2014;34(4):425-36.