The impact of disease activity and interferon-α on the nervous system in systemic lupus erythematosus

Abstract

Background: Systemic lupus erythematosus (SLE) patients, with or without neuropsychiatric SLE (NPSLE), exhibit greater neuronal impairment compared to healthy individuals in terms of neuronal damage, magnet resonance imaging (MRI) changes and cognitive dysfunction. Interferon (IFN)-α is a key immunopathogenic driver of SLE, being persistently overexpressed in the majority of patients. This longitudinal study aimed to investigate whether disease activity and serum IFN-α levels over time were associated with objective findings of neuronal impairment regarding (i) higher plasma neurofilament light (NfL) concentrations, (ii) structural alterations on MRI, and (iii) cognitive dysfunction upon testing.

Methods: Sixty-six consecutive female SLE outpatients were enrolled in a cross-sectional study. Retrospectively, prior visits with concomitant blood samples (n = 199) were selected from the Lund Lupus Cohort database and biobank. Serum IFN-α concentrations were measured using an electrochemiluminescence immunoassay. IFN-α lupus phenotypes were defined as high (n = 24) or low (n = 33) by considering persistent elevations in serum IFN-α concentrations despite low SLE Disease Activity Index-2000 (SLEDAI-2 K) scores. SLEDAI-2 K lupus phenotypes were defined as moderate-high (n = 31) or low (n = 35) based on SLEDAI-2 K scores from all 576 available visits prior to the study. Ongoing neuronal damage was assessed by plasma NfL concentration measurements using Simoa at the 199 visits. Structural MRI alterations and cognitive dysfunction according to the CNS-Vital Signs test battery were the additional outcomes. Multivariate linear mixed-effect, linear regression, and logistic regression models were used for the statistical analyses.

Results: Visits with higher disease activity were associated with higher plasma NfL concentrations (e.g. SLEDAI-2 K total: p = 1.5*10^{- 6}). High compared with low IFN-α lupus phenotype patients displayed more cognitive dysfunction (odds ratio 11.0, p = 0.004), and smaller volumes of total grey matter, caudate nucleus, and thalamus (p = 0.036; p = 0.038; p = 0.023). Moderate-high compared with low SLEDAI-2 K lupus phenotype patients displayed larger white matter lesion volumes and smaller total grey matter and thalamus volumes (p = 0.011; p = 0.041; p = 0.005).

Conclusions: The study suggests that disease activity and IFN-α may drive neuronal affliction in SLE, also in the absence of overt neuropsychiatric symptoms, and that controlling disease activity could improve the cerebral outcome.

Keywords: Cognitive dysfunction; Disease activity; Interferon; MRI; Neurofilament; Systemic lupus erythematosus.

Fig. 1

Study design and data retrieval. A This flow-chart depicts the overall study design including the recruitment of patients for the cross-sectional study and the retrieval of retrospective longitudinal data from the Lund Lupus Cohort database and biobank. B The timeline illustrates the data retrieval for the study. Data retrieval A: In the cross-sectional study patients were assessed extensively by a rheumatologist, neurologist, underwent cognitive testing by a neuropsychologist, MRI, and blood samples. This data was used to assess the associations between the lupus phenotypes and MRI changes & cognitive dysfunction. Data retrieval B: Retrospectively, we chose 199 visits with concomitant blood samples with high and low disease activity, including one visit as early as possible. This data was used for investigating the SLEDAI-2 K and IFN-α associations with repeatedly measured plasma NfL, and to collect samples to determine the IFN-α lupus phenotypes. Data retrieval C: All 576 prior visits with SLEDAI-2 K registered in the database were retrieved. This data was used to determine the SLEDAI-2 K lupus phenotypes

Fig. 2

Plasma NfL concentrations over time. The interconnected dots represent the SLEDAI-2 K score from each visit of the 66 patients. Relatively higher disease activity scores and plasma NfL concentrations were observed in visits close to the diagnosis of SLE

Fig. 3

Main findings. This figure illustrates the main findings of this study. Patients with a phenotype of persistently high serum interferon-α levels had a higher degree of cognitive dysfunction. Both patients with a phenotype of moderate-high SLEDAI-2 K and high interferon-α had a higher degree of structural MRI changes. Neuronal damage assessed by plasma neurofilament light levels was more prominent during visits with higher SLE disease activity