Background/Purpose: Cytokines and neuronal injury markers act as crucial mediators in the bidirectional signaling between the immune system and the brain and may be biomarkers for brain damage. The aim of this study was to determine the prevalence of hyperintense white matter (WM) lesions and to elucidate the possible relationship between biomarkers such as Th1 (IL-12, IFN-γ, TNF-α), Th2 (IL-4,6,10) cytokines and S100β, subunit of high molecular weight neurofilament (NF-H) and antiribosomal P protein antibodies (anti-P) and WM lesions in systemic lupus erythemathosus (SLE) patients.

Methods: Consecutive SLE patients followed at the Rheumatology unit of the State University of Campinas were enrolled in this study. Healthy volunteers, matched by age and sex, were included as control group. A complete clinical, laboratory and neurological evaluation was performed in all subjects. Neurological manifestations were analyzed according to the ACR classification criteria. SLE patients were further assessed for clinical and laboratory SLE manifestations, disease activity [SLE Disease Activity Index (SLEDAI)], damage [Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI)]  and current therapy. WM lesions were analyzed in T2-weighted images (3T Phillips^®scanner) using a semiautomated computer program (Neuroline^®). Th1, Th2 cytokines and S100β, NF-H and anti-P were measured by ELISA using commercial kits.  Data were compared by non-parametric tests. 

Results: One hundred fifty SLE patients (138 women; mean age of 42.03±11.37; range 24-73) and 56 (50 women; mean age of 41.35±12.44; range 18-69) healthy controls were included. WM lesions were identified in 121 (80.67%) SLE patients and in 4 (7.4%) healthy controls (p=0.001). In SLE patients, we observed, predominantly, subcortical lesions (74.67%), followed by periventricular (65.33%), deep WM (59.33%) and cortical (26.67%) lesions. Both the number (N=6549 vs N=27; p=0.001) and the volume of lesions (244109.94cm³ vs 994.65cm³; p<0.001) were significantly increased in SLE patients compared to controls. Significantly increased sera levels of Th1 [IL-12 (p=0.026), IFN-γ (p=0.021), TNF-α (p<0.001)], Th2 [IL-4 (p=0.006), IL-6 (p=0.008) and IL-10 (p<0.001)], S100β (p=0.006), NF-H (p<0.001) and anti-P (p<0.001) were observed in SLE patients compared to controls. We observed an association between the presence of subcortical lesions and IL-10 (p=0.018) and TNF-α (p=0.014). The presence of deep WM lesion was associated with IFN-γ (p=0.04). We also identified an indirect correlation between the volume of subcortical lesions and IL-10 (r=-0.26; p=0.027). We did not observe an association between WM lesions and neuronal injury markers, current corticosteroid dose or any other clinical or laboratory manifestations. 

Conclusion:

TNF-α, IFN-γ and IL-10 levels are associated with WM lesion in SLE, suggesting that peripheral inflammation contributes to WM by triggering an inflammatory response in the microglia. Both Th1 and Th2 cytokines may be useful as biomarkers for brain damage in SLE, once they play a critical role in the interface between the systemic circulation and the brain.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/biomarkers-associated-with-hyperintense-white-matter-lesions-in-systemic-lupus-erythematosus/