Lupus Science & Medicine
INTRODUCTION SLE is a chronic autoimmune disease with up to 20% of patients diagnosed during childhood. Childhood- onset SLE (cSLE) has typical onset in adolescence with high morbidity and mortality, affecting multiple organs including the nervous system, and a more aggressive course compared with those with adult-onset disease. 1 Neuropsychiatric SLE (NPSLE) manifestations affecting the brain are common, affecting approximately 30% of patients with cSLE, 2 often striking during a critical period of adolescent brain development. 3 Among those with NPSLE manifestations, cognitive dysfunction (CD) affects nearly a third, with significant impacts on educa- tion, psychosocial function and overall quality of life. 2–7 CD is defined by the American College of Rheumatology NPSLE nomenclature as a deficit detected in any one of eight neurocognitive domains, with executive function, attention, working memory and psychomotor speed among the most impacted domains in cSLE. 4 5 Yet the biological changes that underlie CD in cSLE are poorly characterised, resulting in challenges for diagnosis and treatment. 3–5 8 Recent insights have linked neuroinflammation with dysregulated signalling of systemic immune cytokines such as type I interferon alpha (IFN- α ), type II interferon gamma (IFN- γ ) and interleukin-6 (IL-6), which can influ- ence central nervous system function through disruption of the blood-brain and blood-cerebrospinal fluid (CSF) barriers, activation of microglia in the central nervous system (CNS), neuronal damage and altered synaptic plasticity, leading to CD. 8–10 Specifically in cSLE, studies suggest that a chronic systemic inflammatory state medi- ated by IFNs may exert direct or indirect disturbances to the developing brain in cSLE. 11 12 Brain tissue inflamma- tion and damage result in the local release of brain injury markers that can be subsequently detected in the blood- stream. 8–10 These markers include serum neurofilament light (sNFL), glial fibrillar acidic protein (GFAP) and Tau, structural proteins associated with neuronal and glial cell damage. 13 sNFL is a component of the axonal skeleton in neurons and is released in the setting of axonal injury. GFAP is an intermediate filament protein almost exclu- sively expressed by astrocytes and is therefore a marker of astrocyte injury. Tau is a microtubule-associated protein and its release from neurons is a marker of neuronal injury and cell death. Serum levels of brain injury markers, including sNFL, GFAP and Tau, have been studied as potential biomarkers of CD in traumatic brain injury, neurodegenerative diseases like Alzheimer’s and neuroinflammatory diseases such as multiple sclerosis. 13–16 While less is known about brain injury markers in SLE, recent studies suggest poten- tial utility for the diagnosis and monitoring of neuropsy- chiatric syndromes, mostly focused on sNFL. In adults with NPSLE, one study found significantly elevated levels of sNFL in patients with NPSLE and focal CNS involve- ment compared with those without NPSLE, 17 and another study found an increase of sNFL and GFAP levels during
the active NPSLE phase with decline following immuno- therapy. 18 sNFL levels have been found to correlate with CSF concentrations 19 and intrathecal sNFL has been associated with IL-6 20 21 in adults with SLE. Furthermore, higher sNFL levels were associated with higher SLE disease activity alongside higher IFN- α levels in associa- tion with CD in a cohort of adults with SLE in the absence of overt neuropsychiatric symptoms. 20 This growing litera- ture supports the potential utility of brain injury markers, even beyond sNFL, for the assessment of neuroinflamma- tion and CD in cSLE, but this is yet to be explored. In this study, we aimed to examine: (1) differences in serum levels of three brain injury markers (sNFL, GFAP and Tau) between cSLE patients and controls, (2) rela- tionships between brain injury markers and CD in cSLE and controls and (3) relationships between brain injury markers, serum cytokine levels (IFN- α , IFN- γ and IL-6) and cSLE disease features.
PARTICIPANTS AND METHODS Study design, participants and setting
We used cross-sectional data from an ongoing prospec- tive longitudinal study of brain health in adolescents with SLE (aged 11–17 years) meeting the Systemic Lupus International Collaborating Clinics (SLICC) or European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) SLE classification criteria 22 23 recruited from the lupus clinic at a Canadian tertiary children’s hospital from January 2020 to December 2023. Age-matched and sex- matched healthy controls who met the inclusion criteria were recruited through study advertisements using formal hospital communication channels. cSLE partici- pants were excluded if they had conditions significantly affecting the ability to complete cognitive tests (eg, severe neurodevelopmental or intellectual disorders, hearing loss, vision problems), were on psychotropic medications, had alcohol or drug use within 24 hours of assessment or had a history of significant head trauma. For controls, the same exclusion criteria were applied, in addition to a known diagnosis of chronic medical conditions and use of steroids. Additionally, all participants had to be fluent in English to complete the study measures, which included neuropsychological assessment and a psychiatric inter- view. The study was approved by The Hospital for Sick Children Research Ethics Board (REB# 1000071306, REB# 1000063027, REB# 1000080072), and all partic- ipants and their parents provided written informed consent and/or assent as appropriate. Demographic variables Demographic characteristics including age at study visit, biological sex and ethnicity were obtained through questionnaires completed by patients and controls. Self- reported ethnicity, where participants chose from a fixed set of categories, was based on the census categories for country of family origin used by Statistics Canada. 24 We
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Mwizerwa O, et al . Lupus Science & Medicine 2026; 13 :e001922. doi:10.1136/lupus-2025-001922
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