To summarize the current evidence on the clinical significance of interleukin (IL)-6 on neuromyelitis optica spectrum disorder (NMOSD).

Th17 cells and their cytokines, especially IL-6, play a key role in NMOSD pathogenesis. IL-6 is under investigation as a biomarker for disease activity, disability, and differential diagnosis.

We searched five databases (PubMed, Embase, Scopus, Web of Science and Google Scholar) up to March 2025 for observational studies on IL-6 and NMOSD. Random-effects meta-analyses were conducted when possible. Risk of bias was assessed with the Newcastle-Ottawa scale.

Sixteen studies (1044 patients) were included. Plasma IL-6 (pg/mL) levels were higher in NMOSD than in healthy-controls (MD = 6.1; 95% CI 1.34–10.86; I²=97.8%), as well as in the CSF (MD = 12.58 pg/mL; 95% CI –3.29 to 28.46; I²=69.8%). Compared with MS, IL-6 was slightly higher in serum (MD = 0.74; 95% CI –1.33 to 2.82; I²=38.1%) and CSF (MD = 11.96; 95% CI –11.58 to 35.51; I²=93%). Compared with MOGAD, IL-6 levels were higher in serum among NMOSD patients (MD = 0.58; 95% CI: 0.01 to 1.14; I² =0%), whereas no significant difference was found in CSF (MD = –181.65; 95% CI: –945.44 to 582.25; I²=36%). Among NMOSD patients, one study reported significantly higher IL-6 levels in AQP4+ vs AQP4–, both in serum (MD = 37.00; 95% CI: 31.13 to 42.87) and CSF (MD = 742.00; 95% CI: 623.96 to 860.04). All studies showed low to moderate risk of bias.

IL-6 levels are elevated in both the serum and CSF of NMOSD patients compared to healthy controls, suggesting its potential as a biomarker. Differences with MS were small and uncertain, while comparisons with MOGAD showed discriminatory potential in serum. Further high-quality studies are needed to clarify its diagnostic value and establish reliable cut-off points.