Objective SLE-patients, with or without nervous system involvement defined by established attribution models of neuropsychiatric SLE, exhibit neuronal affliction marked by elevated plasma neurofilament light (NfL) concentrations, alterations on magnetic resonance imaging (MRI), and cognitive impairment. This longitudinal study aims to investigate the association between general SLE activity and neuronal affliction.

Methods Long-term effects of neuronal affliction were defined by structural alterations on 3 Tesla MRI and cognitive impairment upon neurocognitive testing in 66 female SLE patients. Retrospectively, we selected 199 visits with concomitant blood samples from the Lund SLE research database and biobank. General disease activity was evaluated clinically using SLE Disease Activity Index 2000 (SLEDAI-2K) scores and immunologically by measuring serum interferon (IFN)-α concentration with an electrochemiluminescence immunoassay (MSD). Ongoing neuronal damage was assessed by plasma NfL concentration measurements using a Simoa (Quanterix) assay from the 199 visits. SLE disease activity profiles, IFN-α profile and SLEDAI-2K profile, respectively, were identified for each patient assessed by IFN-α concentrations from all 265 visits (from the time of MRI and neurocognitive testing together with the 199 retrospectively selected visits) and SLEDAI-2K scores from 576 annual visits. Statistical analyses involved multivariate linear mixed-effect, multiple logistic regression, and multiple linear regression models.

Results Higher SLEDAI-2K scores and IFN-α concentrations were both associated with higher plasma NfL concentrations (SLEDAI-2K total, p=1.1*10^-7; IFN-α concentration, p=0.003), adjusted for age, plasma creatinine and treatment. High versus low IFN-α profile patients were more likely to exhibit cognitive impairment (mild to severe dysfunction in any neurocognitive domain 96% vs 51%, odds ratio 20.1, 95% confidence interval 2.4–166, p=0.005) and a higher degree of MRI alterations (smaller volumes of total grey matter, p=0.009; nucleus caudatus, p=0.020; putamen, p=0.036; thalamus, p=0.027). High versus low SLEDAI-2K profile patients expressed a higher degree of MRI alterations (smaller volumes of total grey matter, p=0.023; thalamus, p=0.007; and larger white matter lesion volumes, p=0.017), despite neuropsychiatric activity being present in only four SLEDAI-2K assessments.

Conclusions Systemic disease activity may drive neuronal affliction in SLE patients, even in the absence of overt NP-symptoms. Hence, controlling SLE disease activity is crucial for achieving better cerebral outcomes.