Childhood lupus
and released in the setting of injury to these vulnerable neurons. 12 Our findings suggest that these neurons are particularly affected in adolescents with cSLE. During adolescence, the brain undergoes marked changes in neurogenesis and cortical synaptic remodel- ling or ‘pruning’ during which unmyelinated neurons are actively changing, making this period susceptible to neurodevelopmental insults such as trauma and inflam- mation. 4 33 Supporting this, we found the proportion with CD to be higher in adolescents with cSLE compared to their healthy peers, and CD was associated with higher Tau levels in cSLE. Although serum Tau is not as closely linked to CSF levels as sNFL, these findings parallel studies correlating elevated serum Tau to CD in patients with traumatic brain injury and neurodegenerative condi- tions. 13 14 Together, the high GFAP and Tau levels and associated CD in our cSLE cohort indicate that brain injury occurs during the adolescent period of neurode- velopmental vulnerability, early in their disease course (median disease duration <1 year) and in patients largely (98%) without clinically diagnosed neuropsychiatric involvement. Although this finding needs to be replicated in other cohorts, the implication is that previously under- detected brain injury and dysfunction occurs in adoles- cents with cSLE in the early stages when disease activity is typically the highest. Our analysis provides insight into the role of disease features in brain injury in adolescents with cSLE. While the correlations between brain injury markers and disease activity did not reach statistical significance, our results show weak associations between sNFL, GFAP and Tau and SLEDAI-2K at study visit, and slightly stronger asso- ciations with AMS representing averaged disease activity over the disease course. Furthermore, SDI was weakly associated with sNFL and Tau, supporting a potential link between overall disease damage and neuronal damage in the CNS. As expected, IFN- α , IFN- γ and IL-6 were higher in the cSLE group compared with controls, and sNFL and GFAP showed weak associations with these cytokines. It is notable, however, that the median SLEDAI-2K was low at 2.5 (IQR 2.0, 5.5), only 27% of the cohort had active disease and 9% had damage, which, along with our small sample size, may have affected our ability to detect asso- ciations between disease activity, damage and individual brain injury markers. Our exploratory analysis of cSLE patients with the highest levels across all three brain injury markers found statistically significant relationships with higher disease activity at study visit and averaged over the disease course, and with higher IL-6 levels. These findings are in keeping with studies showing elevated IL-6 in patients with NPSLE. 10 34 Additionally, shorter disease duration and the presence of lupus nephritis neared statistical significance, which is aligned with higher disease activity. It is worth noting that serum Tau can also be expressed from non- CNS tissues such as kidneys, liver and testes 13 ; however, the elevation of both GFAP and Tau and associated CD in the cSLE cohort is supportive of a CNS source of serum Tau.
Table 4 Correlations between brain injury markers and disease characteristics in cSLE sNFL GFAP Tau SLEDAI-2K at study visit r=0.30 p=0.027 r=0.30 p=0.026 r=0.40 p=0.002 AMS, over 1 year r=0.31 p=0.021 r=0.38 p=0.004 r=0.49 p=0.002 SDI
r=0.27 p=0.04 r=0.31 p=0.023 r=0.25 p=0.070 r=0.20 p=0.151 r=0.30 p=0.025 r=0.13 p=0.348
r=0.33 p=0.012 r=0.05 p=0.701 r=0.04 p=0.70 r=0.18 p=0.194 r=0.27 p=0.045 r=0.15 p=0.273
r=0.22 p=0.10 r=0.27 p=0.048 r=0.28 p=0.034 r=0.28 p=0.042 r=0.30 p=0.027 r=−0.14 p=0.315
IFN- α
IFN- γ
IL-6
Current GC dose
Cumulative GC exposure
Tau, IFN- α , IFN- γ and IL-6 and a high proportion with CD compared with age-matched and sex-matched controls, despite the majority lacking a clinical NPSLE diagnosis. In addition, Tau was associated with CD in patients with cSLE, and those with the highest levels of brain injury markers (across sNFL, GFAP and Tau) had higher disease activity, serum IL-6 levels and GC dose. Our novel find- ings in cSLE add to the growing literature indicating a link between systemic inflammation, brain injury and CD in SLE, even in those without recognised NPSLE. The brain injury markers assessed in this study repre- sent different aspects of cellular brain injury, and our findings shed light on potential underlying mechanisms for brain involvement in cSLE. While sNFL, a marker of axonal injury that tracks closely with CSF levels and has been the most implicated in neuropsychiatric features of SLE, 17–19 21 we did not find differences in sNFL. Rather, GFAP and Tau were significantly elevated in cSLE compared with controls. GFAP is a specific marker of injury to astrocytes, which are abundant in the brain to provide neuro-supportive functions; however, under pathological inflammatory conditions in the setting of activated microglia, astrocytes change into a neurotoxic phenotype, reflected by high GFAP levels. 13 32 Unlike sNFL, which is highly expressed in large-calibre myelin- ated neurons that extend subcortically, Tau is predomi- nantly expressed in unmyelinated neurons in the cortex Shown are relationships between brain injury markers and disease characteristics in patients with cSLE. Spearman correlations in bold are significant for p<0.05. AMS, adjusted mean SLEDAI-2K; cSLE, childhood-onset SLE; GC, glucocorticoids; GFAP, glial fibrillar acidic protein; IFN- α , interferon alpha; IFN- γ , interferon gamma; IL-6, interluekin-6; SDI, Systemic Lupus International Collaborating Clinics/ American College of Rheumatology (SLICC/ACR) Damage Index; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000; sNFL, serum neurofilament light.
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Mwizerwa O, et al . Lupus Science & Medicine 2026; 13 :e001922. doi:10.1136/lupus-2025-001922
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